Female and male mice deficient in IL-10 production by targeted disruption of the IL-10 gene were infected with Plasmodium chabaudi chabaudi (AS) blood-stage parasites. Both male and female mutant mice exhibited more severe signs of disease than did +/+ or heterozygous control mice. Female defective mice also displayed an increased mortality; 56% of mice died within 20 days of infection. Mortality did not appear to be due to a fulminating parasitemia as death occurred at different levels of parasitemia in the individual mice. The acute infection was accompanied by an enhanced Th1 IFN-gamma response. This response was retained in the chronic phase of infection of both male and female mutant mice, whereas in controls the responding CD4+ T cells were predominantly Th2 cells secreting IL-4. The data suggest that IL-10 regulates the inflammatory response to the parasite and that in its absence the combined effects of malaria toxins and the sustained or enhanced IFN-gamma response lead to increased pathology. In the case of female mice absence of IL-10 is sufficient to induce a lethal endotoxin-like reaction.