After five serial passages of Candida albicans SC5314 through murine spleens by intravenous inoculation, we recovered a respiratory mutant (strain P5) that exhibited reduced colony size, stunted growth in glucose-deficient media, increased oxygen consumption and defective carbohydrate assimilation. Strain P5 was indistinguishable from SC5314 by DNA typing methods, but had a greater concentration of mitochondria by SYTO18 staining. Treatment with various inhibitors demonstrated that strain P5's electron transport chain was intact and oxidative phosphorylation was uncoupled. During disseminated candidiasis, the mutant did not kill mice or cause extensive damage to kidneys. The burden of strain P5 within kidneys on the first 3 days of disseminated candidiasis was significantly reduced. By days 28 and 60, it was similar to that at the time of death among mice infected with SC5314, suggesting that the mutant persisted and proliferated without killing mice. Strain P5 was resistant to phagocytosis by neutrophils and macrophages. It was also significantly more resistant to paraquat, suggesting that it is able to neutralize reactive oxygen species. Our findings indicate that regulation of respiration influences the interaction between C. albicans and the host. Uncoupling of oxidative phosphorylation might be a mechanism by which the organism adapts to stressful host environments.