Twenty-nine immunocompromised patients were treated with intravenous trimethoprim-sulfamethoxazole for possible Pneumocystis carinii pneumonia. The diagnosis was established in 15 severely hypoxemic patients with lymphoreticular malignancy or cardiac transplants by open lung biopsy or transthoracic needle aspirate. In 13 (87 percent) of the 15, the response to therapy was rapid. They became afebrile in a mean of 2.1 days, showed improved arterial blood oxygenation in 4.7 days and improvements on the chest roentgenogram in 4.3 days. Eight (53 percent) of the 15 survived and were clinically cured. Five other patients with documented P. carinii infection improved clinically but subsequently died of other causes. Postmortem examination in these showed no P. carinii cysts. Two patients with P. carinii pneumonia died soon after therapy was started and had P. carinii cysts in lung tissue at autopsy. The combined clinical and microbiologic response of 87 percent equals or exceeds that of other reported treatment regimens. Intravenous trimethoprim-sulfamethoxazole may, therefore, be the most ideal therapy for severely ill adults with P. carinii pneumonia. Second lung biopsies in 12 patients on therapy showed that P. carinii cysts were rarely found after several days of treatment. This suggests that lung tissue may be falsely negative for P. carinii cysts in persons treated empirically but who later undergo lung biopsy.