diff --git a/lldb/source/API/SystemInitializerFull.cpp b/lldb/source/API/SystemInitializerFull.cpp
--- a/lldb/source/API/SystemInitializerFull.cpp
+++ b/lldb/source/API/SystemInitializerFull.cpp
@@ -15,6 +15,7 @@
 #include "lldb/Initialization/SystemInitializerCommon.h"
 #include "lldb/Interpreter/CommandInterpreter.h"
 #include "lldb/Target/ProcessTrace.h"
+#include "lldb/Utility/Reproducer.h"
 #include "lldb/Utility/Timer.h"
 #include "llvm/Support/TargetSelect.h"
 
@@ -34,8 +35,16 @@
 SystemInitializerFull::~SystemInitializerFull() = default;
 
 llvm::Error SystemInitializerFull::Initialize() {
-  if (auto e = SystemInitializerCommon::Initialize())
-    return e;
+  llvm::Error error = SystemInitializerCommon::Initialize();
+  if (error) {
+    // During active replay, the ::Initialize call is replayed like any other
+    // SB API call and the return value is ignored. Since we can't intercept
+    // this, we terminate here before the uninitialized debugger inevitably
+    // crashes.
+    if (repro::Reproducer::Instance().IsReplaying())
+      llvm::report_fatal_error("system initialization failed");
+    return error;
+  }
 
   // Initialize LLVM and Clang
   llvm::InitializeAllTargets();