Pulmonary infections with Pneumocystis carinii are an important cause of morbidity and mortality in patients with AIDS. P. carinii infections are seen in patients with decreased numbers of helper T lymphocytes, suggesting that these cells are important in preventing infection. To test this hypothesis, we sought to establish experimental infection with P. carinii in mice selectively depleted of helper T lymphocytes. Weekly injections of a monoclonal anti-CD4 antibody produced sustained depletion of helper T lymphocytes from blood and lymphoid organs. To establish pulmonary infection, lymphocyte-depleted mice were then given intratracheal inoculations of P. carinii organisms derived from the lungs of chronically infected athymic mice. Pulmonary infection with P. carinii was demonstrable in the antibody-treated mice and was centered around the conducting airways. Infection was persistent for up to 3 mo with continued antibody treatments, and yet could be cleared from the lungs if antibody treatments were discontinued. This experimental model of P. carinii infection permits the study of infection associated with a specific immune defect and implicates the helper T lymphocyte as a critical cell in host defense against this pathogen.