Pneumocystis pneumonia is a major cause of death for AIDS patients. Over the past 20 years almost nothing has been learned about the causative organisms, Pneumocystis carinii. In a collaborative effort, an in vitro system was established which identified trimetrexate as a potent dihydrofolate reductase inhibitor for pneumocystis, far more potent than currently available drugs. In a clinical trial for AIDS patients with pneumocystis pneumonia, trimetrexate alone and trimetrexate with sulfa gave excellent response rates when used as initial therapy and when used for patients who had failed conventional therapy. Toxicity was minimal. Large multicenter trials to compare trimetrexate with conventional therapy started 8/88. NIH is coordinating the national study that compares trimetrexate to other therapies for patients who are failing conventional approaches. NIH is also initiating trials that look at combinations of trimetrexate with either dapsone or aerosolized pentamidine to determine if combination therapy is more effective, but as well tolerated as single drug therapy. The importance of this project is the identification of new drugs to treat a major cause of death among AIDS patients.