Monte Carlo (MC) simulation has become an important tool for characterizing and evaluating imaging systems and reconstruction algorithms. In this work, we combined two MC codes-Monte Carlo N-particle transport code system (MCNP) and simulation system for emission tomography (SimSET)-using the advantages of each to produce a simulation tool that is efficient enough to generate single photon emission computed tomography (SPECT) data. The new SimSET-MCNP method allows the use of voxelized three-dimensional (3-D) phantoms and models photon propagation inside collimator-detector systems. This combination provides a tool for evaluating compensation methods applied to imaging of agents where medium- and high-energy photons are important. To validate the new tool, we compared simulated projections of a sphere containing I-123 water solution embedded in a cylindrical water-filled phantom with experimentally measured projections and simulations using SimSET and MCNP alone. Using these data, we compared profiles through the projection data, energy spectra, and relative number of photons in four projection views. The agreement with experiment was good, with disagreements of the order of a few percent. In addition, for the MC simulations, we classified detected photons based on whether they scattered in the phantom, whether they passed through the collimator holes, penetrated the septa, or scattered in the collimator, and whether they resulted from 159-keV or high-energy photons. For all these classes of photons, there was excellent agreement between SimSET-MCNP and MCNP. Finally, we evaluated the new combination in terms of simulation time and found it significantly more efficient than MCNP alone. We conclude that the new simulation tool works and allows the generation of SPECT data using voxelized phantoms for cases when medium- and high-energy photons are important.