Pneumocystis carinii is an important cause of pneumonia in immunocompromised hosts. Both cellular and humoral immunity seem important in resistance to this pathogen, but the specific role of each component is poorly understood. An outbreak of P. carinii pneumonia in transgenic B cell-deficient mice (µMT) was studied. Over 4 months, >50% of 41 µMT/µMT mice maintained in a sterile environment died of pneumonia. Some mice had concurrent infection with Pasteurella pneumotropica. Homozygous µMT/µMT mice had no detectable serum immunoglobulins, while their heterozygous µMT/+ counterparts had normal levels of IgM, IgG, and IgA and did not develop pneumonia. The infection was controlled by treating the mice with trimethoprim-sulfamethoxazole, and the pathogen was eliminated by cesarean rederivation. These observations suggest an important role for B cells in the host defense against P. carinii.