Functional full-system simulators are powerful and versatile research tools for accelerating architectural exploration and advanced software development. Their main shortcoming is limited throughput when simulating large multiprocessor systems with hundreds or thousands of processors or when instrumentation is introduced. We propose the PROTOFLEX simulation architecture, which uses FPGAs to accelerate full-system multiprocessor simulation and to facilitate high-performance instrumentation. Prior FPGA approaches that prototype a complete system in hardware are either too complex when scaling to large-scale configurations or require significant effort to provide full-system support. In contrast, PROTOFLEX virtualizes the execution of many logical processors onto a consolidated number of multiple-context execution engines on the FPGA. Through virtualization, the number of engines can be judiciously scaled, as needed, to deliver on necessary simulation performance at a large savings in complexity. Further, to achieve low-complexity full-system support, a hybrid simulation technique called transplanting allows implementing in the FPGA only the frequently encountered behaviors, while a software simulator preserves the abstraction of a complete system. We have created a first instance of the PROTOFLEX simulation architecture, which is an FPGAbased, full-system functional simulator for a 16-way UltraSPARC III symmetric multiprocessor server, hosted on a single Xilinx Virtex-II XCV2P70 FPGA. On average, the simulator achieves a 38x speedup (and as high as 49×) over comparable software simulation across a suite of applications, including OLTP on a commercial database server. We also demonstrate the advantages of minimal-overhead FPGA-accelerated instrumentation through a CMP cache simulation techniquethat runs orders-of-magnitude faster than software.