The clinical experience of human immunodeficiency virus (HIV) + patients treated with oral atovaquone for acute Pneumocytstis carinii pneumonia (PCP) under a Treatment Investigational New Drug (IND) protocol (mild or moderate PCP) and an Open-Label Study protocol (severe PCP) was evaluated. A total of 940 patients intolerant of or unresponsive to trimethoprimsulfamethoxazole were enrolled from private practices, clinics, and institutional HIV treatment centers in the United States. Demographics data and the history and severity of PCP were collected at enrollment. The number of therapy days, adverse experiences, clinical response to therapy, and mortality were collected at day 21. Reporting of serious, unexpected adverse experiences attributable to therapy was required. Of the 760 (96%) patients with mild to moderate disease for whom follow-up observation was complete, 591 (78%) responded clinically to treatment, 177 patients (23%) discontinued treatment prematurely, and 50 patients (7%) died. Of the 140 patients (95%) with severe PCP with follow-up data, 79 (56%) responded to treatment, 45 (32%) discontinued treatment early, and 53 patients (38%) died. Adverse events that resulted in temporary or permanent discontinuation of therapy included diarrhea, vomiting, elevated liver enzyme levels, nausea, and fever. No serious unexpected adverse events attributable to the drug were reported. The treatment IND mechanism enabled a large number of patients with acute PCP to be treated with this experimental therapy while the drug was under regulatory view.