Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA(+/+) mice and SRA(-/-) mice were infected intratracheally with C. neoformans. Results show that infection of SRA(-/-) mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA(+/+) mice. Improved fungal clearance in SRA(-/-) mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4(+) T cells and CD11b(+) dendritic cells. Additional parameters were consistent with enhanced anticryptococcal immunity in the infected SRA(-/-) mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.