System and method of compiling a program having a mixture of host code and device code to enable Profile Guided Optimization (PGO) for device code execution. An exemplary integrated compiler can compile source code programmed to be executed by a host processor (e.g., CPU) and a co-processor (e.g., a GPU) concurrently. The compilation can generate an instrumented executable code which includes: profile instrumentation counters for the device functions; and instructions for the host processor to allocate and initialize device memory for the counters and to retrieve collected profile information from the device memory to generate instrumentation output. The output is fed back to the compiler for compiling the source code a second time to generate optimized executable code for the device functions defined in the source code.