Epidemiological and clinical studies have confirmed that coccidioidomycosis is more severe in African American and Filipino patients than in Caucasians, suggesting a genetic basis for susceptibility in humans. We discovered that inbred strains of mice also vary greatly in their susceptibility to Coccidioides immitis infections, and although resistance is the dominant phenotype, it is a multigenic trait in mice. We found a strong direct correlation between susceptibility in mice and the amount of IL-10 made in response to infection. We then showed that IL-10-deficient mice are much more resistant to infection than the parent C57BL/6 strain. Finally, we showed that genetically resistant mice that are transgenic for IL-10 and so overproduce that cytokine are more susceptible to C. immitis. This is in part due to suppression of NOS2 expression by IL-10.