Four hundred fifty volunteers participated in a placebo-controlled, double-blind, randomized trial of the prophylactic effects of rimantadine and amantadine during an outbreak of influenza A. The subjects received drugs orally at a dose of 100 mg twice a day for six weeks. Influenza-like illness occurred in 41 per cent of the subjects receiving placebo but in only 14 per cent of those receiving rimantadine and 9 per cent of these receiving amantadine (P less than 0.001 for either drug vs. placebo). Laboratory-documented influenza occurred in 21 per cent of placebo recipients, 3 per cent of rimantadine recipients, and 2 per cent of amantadine recipients (P less than 0.001). These findings represent efficacy rates of 85 per cent for rimantadine and 91 per cent for amantadine, as compared with placebo. More recipients of amantadine (13 per cent) than recipients of rimantadine (6 per cent; P less than 0.05) or placebo (4 per cent; P less than 0.01) withdrew from the study because of central-nervous-system side effects. On the basis of this study, rimantadine appears to be the drug of choice for the prophylaxis of influenza A.