Cryptococcus neoformans causes severe, and often fatal, disease (cryptococcosis) in immunocompromised patients, particularly in those with HIV/AIDS. Although resistance to cryptococcosis requires intact T-cell immunity, a possible role for antibody/B cells in protection against natural disease has not been definitively established. Previous studies of the antibody response to the C. neoformans capsular polysaccharide glucuronoxylomannan (GXM) have demonstrated that patients who are at increased risk for cryptococcosis have lower serum levels of GXM-reactive IgM than those who are not at risk, leading to the hypothesis that IgM might contribute to resistance to cryptococcosis. To determine the influence of IgM on susceptibility to systemic cryptococcosis in a murine model, we compared the survival of mice deficient in serum IgM (secretory IgM deficient [sIgM(-/-)]) and C57BL/6 x 129Sv (control) mice after intraperitoneal infection with C. neoformans strain 24067 and analyzed the splenic B- and T-cell subsets by flow cytometry and the serum and splenic cytokine/chemokine and serum antibody profiles of each mouse strain. The results showed that sIgM(-/-) mice survived significantly longer than control mice when challenged with 10(5) CFU of C. neoformans 24067. Naïve sIgM(-/-) mice had higher levels of B-1 (CD5(+)) B cells, proinflammatory mediators (interleukin-6 [IL-6], IL-1beta, MIP-1beta, tumor necrosis factor alpha [TNF-alpha], and gamma interferon [IFN-gamma]), and anti-inflammatory mediators (IL-10 and IL-13) and significantly higher titers of GXM-specific IgG2a 3 weeks postinfection. In addition, CD5(+) splenocytes from both mouse strains had fungicidal activity against C. neoformans. Taken together, these results suggest that the inflammatory milieu in sIgM(-/-) mice might confer enhanced resistance to systemic cryptococcosis, stemming in part from the antifungal activity of B-1 B cells.