Pneumocystis carinii is the most important pulmonary pathogen in patients with the acquired immunodeficiency syndrome, but host defenses against P. carinii are not well characterized. We recently reported an experimental model of P. carinii infection, in which mice selectively depleted of CD4+ lymphocytes develop pulmonary infection after inoculation with P. carinii. In the current study, we compared lung inflammatory responses to P. carinii inoculation in CD4-depleted mice and in normal mice in order to further characterize host defenses against P. carinii. We hypothesized that depletion of CD4+ lymphocytes would prevent recruitment and activation of inflammatory cells in the lungs of these mice, allowing progressive infection with P. carinii. We found that CD4-depleted mice were unable to recruit CD4+ lymphocytes into their lungs and developed progressive infection with P. carinii, but mounted exuberant inflammatory responses to the organisms. These inflammatory responses were characterized by perivascular infiltration with mononuclear cells, increases in cell numbers in bronchoalveolar lavage (particularly CD8+ lymphocytes), and activation of alveolar macrophages (enhanced Ia antigen expression). In contrast, normal mice recruited CD4+ lymphocytes into their lungs and eliminated organisms with only minimal inflammatory responses. We conclude that depletion of CD4+ lymphocytes does not prevent the recruitment and activation of inflammatory cells in the lung. These inflammatory responses occur by mechanisms independent of CD4+ lymphocytes and are insufficient to provide effective host defense against P. carinii.