The effect of simplifications in nuclear fuel depletion analysis as well as the effect of cross-section uncertainties were evaluated as to their impact upon material attractiveness for weapons diversion purposes. The effect of simplified depletion models for material attractiveness evaluation was evaluated through a comparison of pressurized water reactor fuel for several benchmark cases, using experimentally measured values along with a two-dimensional lattice physics model (TRITON) and a point depletion model (ORIGEN-S). Simplifications such as the use of the ORIGEN-S depletion libraries and assumptions of homogeneous core enrichment were found to have a negligible impact on material attractiveness evaluation, particularly relative to uncertainties in experimental measurements; additionally, simplified irradiation power histories do not introduce unacceptable errors into the attractiveness evaluation. Finally, the overall sensitivity of material attractiveness and associated uncertainty was found to be greater for transuranic mixtures compared to plutonium as a function of both burnup and decay time; however, associated uncertainties are generally small and not prohibitive to material attractiveness discrimination. As a result, the use of simplified depletion models such as ORIGEN-S appears to be well justified for use in material attractiveness evaluation for proliferation resistance studies.