diff --git a/clang-tools-extra/clangd/IncludeCleaner.h b/clang-tools-extra/clangd/IncludeCleaner.h
--- a/clang-tools-extra/clangd/IncludeCleaner.h
+++ b/clang-tools-extra/clangd/IncludeCleaner.h
@@ -24,6 +24,7 @@
 #include "Headers.h"
 #include "ParsedAST.h"
 #include "clang/Basic/SourceLocation.h"
+#include "clang/Lex/HeaderSearch.h"
 #include "llvm/ADT/DenseSet.h"
 #include <vector>
 
@@ -55,10 +56,12 @@
                                            const SourceManager &SM);
 
 /// Maps FileIDs to the internal IncludeStructure representation (HeaderIDs).
-/// FileIDs that are not true files (<built-in> etc) are dropped.
+/// FileIDs that are not true files (<built-in> etc) and headers without
+/// include guards are dropped.
 llvm::DenseSet<IncludeStructure::HeaderID>
 translateToHeaderIDs(const llvm::DenseSet<FileID> &Files,
-                     const IncludeStructure &Includes, const SourceManager &SM);
+                     const IncludeStructure &Includes, const SourceManager &SM,
+                     HeaderSearch &HeaderSearch);
 
 /// Retrieves headers that are referenced from the main file but not used.
 std::vector<const Inclusion *>
diff --git a/clang-tools-extra/clangd/IncludeCleaner.cpp b/clang-tools-extra/clangd/IncludeCleaner.cpp
--- a/clang-tools-extra/clangd/IncludeCleaner.cpp
+++ b/clang-tools-extra/clangd/IncludeCleaner.cpp
@@ -14,6 +14,8 @@
 #include "support/Trace.h"
 #include "clang/AST/RecursiveASTVisitor.h"
 #include "clang/Basic/SourceLocation.h"
+#include "clang/Lex/HeaderSearch.h"
+#include "clang/Lex/Preprocessor.h"
 #include "clang/Tooling/Syntax/Tokens.h"
 #include "llvm/Support/FormatVariadic.h"
 #include "llvm/Support/Path.h"
@@ -251,8 +253,8 @@
 
 llvm::DenseSet<IncludeStructure::HeaderID>
 translateToHeaderIDs(const llvm::DenseSet<FileID> &Files,
-                     const IncludeStructure &Includes,
-                     const SourceManager &SM) {
+                     const IncludeStructure &Includes, const SourceManager &SM,
+                     HeaderSearch &HeaderInfo) {
   llvm::DenseSet<IncludeStructure::HeaderID> TranslatedHeaderIDs;
   TranslatedHeaderIDs.reserve(Files.size());
   for (FileID FID : Files) {
@@ -261,6 +263,13 @@
       assert(isSpecialBuffer(FID, SM));
       continue;
     }
+    // Headers without include guards have side effects and are not
+    // self-contained, skip them.
+    if (!HeaderInfo.isFileMultipleIncludeGuarded(FE)) {
+      dlog("{0} doesn't have header guard and will not be considered unused",
+           FE->getName());
+      continue;
+    }
     const auto File = Includes.getID(FE);
     assert(File);
     TranslatedHeaderIDs.insert(*File);
@@ -272,8 +281,9 @@
   const auto &SM = AST.getSourceManager();
 
   auto Refs = findReferencedLocations(AST);
-  auto ReferencedFiles = translateToHeaderIDs(findReferencedFiles(Refs, SM),
-                                              AST.getIncludeStructure(), SM);
+  auto ReferencedFiles = translateToHeaderIDs(
+      findReferencedFiles(Refs, SM), AST.getIncludeStructure(), SM,
+      AST.getPreprocessor().getHeaderSearchInfo());
   return getUnused(AST.getIncludeStructure(), ReferencedFiles);
 }
 
diff --git a/clang-tools-extra/clangd/unittests/DiagnosticsTests.cpp b/clang-tools-extra/clangd/unittests/DiagnosticsTests.cpp
--- a/clang-tools-extra/clangd/unittests/DiagnosticsTests.cpp
+++ b/clang-tools-extra/clangd/unittests/DiagnosticsTests.cpp
@@ -1494,9 +1494,11 @@
   TestTU TU;
   TU.Code = Test.code().str();
   TU.AdditionalFiles["unused.h"] = R"cpp(
+    #pragma once
     void unused() {}
   )cpp";
   TU.AdditionalFiles["used.h"] = R"cpp(
+    #pragma once
     void used() {}
   )cpp";
   TU.AdditionalFiles["system/system_header.h"] = "";
diff --git a/clang-tools-extra/clangd/unittests/IncludeCleanerTests.cpp b/clang-tools-extra/clangd/unittests/IncludeCleanerTests.cpp
--- a/clang-tools-extra/clangd/unittests/IncludeCleanerTests.cpp
+++ b/clang-tools-extra/clangd/unittests/IncludeCleanerTests.cpp
@@ -9,6 +9,7 @@
 #include "Annotations.h"
 #include "IncludeCleaner.h"
 #include "TestTU.h"
+#include "llvm/ADT/StringRef.h"
 #include "gmock/gmock.h"
 #include "gtest/gtest.h"
 
@@ -16,6 +17,10 @@
 namespace clangd {
 namespace {
 
+std::string guard(llvm::StringRef Code) {
+  return "#pragma once\n" + Code.str();
+}
+
 using ::testing::ElementsAre;
 using ::testing::UnorderedElementsAre;
 
@@ -216,13 +221,13 @@
   // Build expected ast with symbols coming from headers.
   TestTU TU;
   TU.Filename = "foo.cpp";
-  TU.AdditionalFiles["foo.h"] = "void foo();";
-  TU.AdditionalFiles["a.h"] = "void a();";
-  TU.AdditionalFiles["b.h"] = "void b();";
-  TU.AdditionalFiles["dir/c.h"] = "void c();";
-  TU.AdditionalFiles["unused.h"] = "void unused();";
-  TU.AdditionalFiles["dir/unused.h"] = "void dirUnused();";
-  TU.AdditionalFiles["system/system_header.h"] = "";
+  TU.AdditionalFiles["foo.h"] = guard("void foo();");
+  TU.AdditionalFiles["a.h"] = guard("void a();");
+  TU.AdditionalFiles["b.h"] = guard("void b();");
+  TU.AdditionalFiles["dir/c.h"] = guard("void c();");
+  TU.AdditionalFiles["unused.h"] = guard("void unused();");
+  TU.AdditionalFiles["dir/unused.h"] = guard("void dirUnused();");
+  TU.AdditionalFiles["system/system_header.h"] = guard("");
   TU.ExtraArgs.push_back("-I" + testPath("dir"));
   TU.ExtraArgs.push_back("-isystem" + testPath("system"));
   TU.Code = MainFile.str();
@@ -252,6 +257,9 @@
   // ScratchBuffer with `flags::FLAGS_FOO` that will have FileID but not
   // FileEntry.
   TU.AdditionalFiles["macros.h"] = R"cpp(
+    #ifndef MACROS_H
+    #define MACROS_H
+
     #define DEFINE_FLAG(X) \
     namespace flags { \
     int FLAGS_##X; \
@@ -261,6 +269,8 @@
 
     #define ab x
     #define concat(x, y) x##y
+
+    #endif // MACROS_H
     )cpp";
   TU.ExtraArgs = {"-DCLI=42"};
   ParsedAST AST = TU.build();
@@ -278,7 +288,9 @@
                                    testPath("macros.h")));
 
   // Should not crash due to FileIDs that are not headers.
-  auto ReferencedHeaders = translateToHeaderIDs(ReferencedFiles, Includes, SM);
+  auto ReferencedHeaders =
+      translateToHeaderIDs(ReferencedFiles, Includes, SM,
+                           AST.getPreprocessor().getHeaderSearchInfo());
   std::vector<llvm::StringRef> ReferencedHeaderNames;
   for (IncludeStructure::HeaderID HID : ReferencedHeaders)
     ReferencedHeaderNames.push_back(Includes.getRealPath(HID));