A system and method are provided for inlining a program call between processes executing under separate ISAs (Instruction Set Architectures) within a system virtual machine. The system virtual machine hosts any number of virtual operating system instances, each of which may execute any number of applications. The system virtual machine interprets or dynamically compiles not only application code executing under virtual operating systems, but also the virtual operating systems. For a program call that crosses ISA boundaries, the virtual machine assembles an intermediate representation (IR) graph that spans the boundary. Region nodes corresponding to code on both sides of the call are enhanced with information identifying the virtual ISA of the code. The IR is optimized and used to generate instructions in a native ISA (Instruction Set Architecture) of the virtual machine. Individual instructions are configured and executed (or emulated) to perform as they would within the virtual ISA.