The relative roles of top-down and bottom-up forces in affecting disease prevalence in wild hosts is important for understanding disease dynamics and human disease risk. We found that the prevalence of Sin Nombre virus (SNV), the agent of a severe disease in humans (hantavirus pulmonary syndrome), in island deer mice from the eight California Channel Islands was greater with increased precipitation (a measure of productivity), greater island area, and fewer species of rodent predators. In finding a strong signal of the ecological forces affecting SNV prevalence, our work highlights the need for future work to understand the relative importance of average rodent density, population fluctuations, behavior, and specialist predators as they affect SNV prevalence. In addition to illustrating the importance of both bottom-up and top-down limitation of disease prevalence, our results suggest that predator richness may have important bearing on the risk of exposure to animal-borne diseases that affect humans.