BACKGROUND: Current recommendations for prophylaxis of Pneumocystis carinii pneumonia (PCP) are based on data from patients who have had at least one episode of PCP (secondary prevention). We designed a study to determine the efficacy and side effects of inhaled pentamidine in the primary prevention of PCP. METHODS: Two hundred twenty-three patients sero-positive for human immunodeficiency virus (HIV) who had the acquired immunodeficiency syndrome (AIDS) but not PCP, who had advanced AIDS-related complex, or who had less than 0.2 x 10(9) CD4-positive lymphocytes per liter received either 300 mg of pentamidine isethionate or 300 mg of sodium isethionate every 28 days by inhaler. The proportion of patients surviving without PCP was analyzed with the log-rank test as a function of time spent in the trial, according to the intention to treat with either placebo or pentamidine. RESULTS: The third of five planned interim analyses showed a significant difference in the occurrence of PCP, with 8 cases in pentamidine group and 23 in the placebo group (nominal P value = 0.0021). There were no deaths within 60 days of the diagnosis of PCP and no significant differences in survival between groups. Approximately 53 inhalations were needed to prevent one episode of pneumonia. Thirty-eight of 114 patients given pentamidine (33 percent) and 7 of 109 given placebo (6 percent) had moderate-to-severe coughing during inhalations (two-tailed P less than 0.00001), which caused 4 patients given pentamidine (3.5 percent) to discontinue taking it. CONCLUSIONS: A dose of 300 mg of aerosolized pentamidine given every four weeks was well tolerated and 60 to 70 percent effective in preventing a first episode of PCP in patients with HIV infection.