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ABSTRACT Cryptococcosis remains a significant threat to human health. While the popular C57BL/6J mouse model of cryptococcosis has some advantages, there are some serious shortcomings that limit the ability of researchers to address the disease. Since humans are resistant to environmental cryptococcal infection until rendered immunodeficient while C57BL/6J mice are innately susceptible, we screened 15 inbred mouse strains for resistance to Cryptococcus infection. The SJL/J mouse strain was unusually resistant to several virulent strains of Cryptococcus while the closely related FVB/J strain was susceptible. The infection pathobiology in SJL/J mice and susceptible mice was similar for the first 7–10 days then markedly diverged toward pathogen clearance. Interferon-gamma (IFN-γ) expression was critical for SJL/J resistance while tumor necrosis factor-alpha was also important. Both CD4 and CD8 T cells produced IFN-γ and were collectively critical. While IL-17 and associated cytokines were expressed in SJL/J mice, IL-17 inhibition did not affect the outcome of infection. Unlike the C57BL/6J, infected SJL/J mice failed to express Th2/atopy-type cytokines even when rendered susceptible by IFN-γ blockade or infection with an alternative fatal cryptococcal strain virulent in SJL/J. These data suggest that the atopic-type response typically associated with the C57BL/6J model is not critical for susceptibility. The productive immune response in SJL/J mice resulted in immune memory that protected mice from reinfection. The SJL/J cryptococcal resistance phenotype was associated with a strong genetic linkage from regions located in chromosomes 2 and 11 suggesting strain-specific modifiers contribute to disease severity. Thus, SJL/J mice are an exciting alternative animal model for cryptococcal pathobiology. IMPORTANCE Cryptococcosis studies often utilize the common C57BL/6J mouse model. Unfortunately, infection in these mice fails to replicate the basic course of human disease, particularly hampering immunological studies. This work demonstrates that SJL/J mice can recapitulate human infection better than other mouse strains. The immunological response to Cryptococcus infection in SJL/J mice was markedly different from C57BL/6J and much more productive in combating this infection. Characterization of infected mice demonstrated strain-specific genetic linkage and differential regulation of multiple important immune-relevant genes in response to Cryptococcus infection. While our results validate many of the previously identified immunological features of cryptococcosis, we also demonstrate limitations from previous mouse models as they may be less translatable to human disease. We concluded that SJL/J mice more faithfully recapitulate human cryptococcosis serving as an exciting new animal model for immunological and genetic studies.