Mathematical models of HPV vaccine effectiveness and cost-effectiveness have produced conflicting results. The aim of this study was to use mathematical models to compare and isolate the impact of the assumptions most commonly made when modeling the effectiveness of HPV vaccines. Our results clearly show that differences in how we model natural immunity, herd immunity, partnership duration, HPV types, and waning of vaccine protection lead to important differences in the predicted effectiveness of HPV vaccines. These results are important and useful to assist modelers/health economists in choosing the appropriate level of complexity to include in their models, provide epidemiologists with insight on key data necessary to increase the robustness of model predictions, and help decision makers better understand the reasons underlying conflicting results from HPV models.