The relative toxicities of amantadine and rimantadine were compared in a double-blind, placebo-controlled study involving healthy adults. In separate studies, drugs were administered at a dosage of 200 mg/day (52 volunteers) or 300 mg/day (196 volunteers) Clinical trials have documented that amantadine hydrochloride (7,11,14,17,18,22 483, 1978) and rimantadine hydrochloride (6,11,26,33) are effective prophylactic and therapeutic drugs in influenza A virus infections. Several in vitro (10, 31) and animal (1, 28, 31) models have suggested that rimantadine has greater antiviral activity than amantadine against influenza A viruses. However, the relative effectiveness of the two compounds in human infections has not been fully defined.Available information regarding the relative toxicities of the two compounds in humans is also inconclusive. Most studies of amantadine prophylaxis with a dose of 200 mg/day have described few side effects (14,22,25 484, 1978). However, recent work found substantial rates of subjective central nervous system (CNS) complaints and possible adverse effects on objective measures of psychomotor performance at this dosage (4). Rimantadine has been considered to be better tolerated in humans (11), but several studies (25; Noble et al., 18th ICAAC, abstr. no. 484) have not confirmed this observation. Optimal antiviral and therapeutic effects in treatment of influenza A virus infections would likely be achieved with administration of higher drug dosages. If lower drug toxicity were confirmed for rimantadine, then it would be an appropriate candidate for future chemotherapy studies in which higher dosages are used.The present study was undertaken to compare the relative toxicities of equivalent doses of amantadine and rimantadine. Both subjective and objective measures of potential drug side effects were studied at conventional (200 mg/ day) and higher (300 mg/day) dosages in healthy adults. Our results indicated that both drugs were well tolerated at the lower dosage, but that rimantadine was significantly better tolerated than amantadine at a dosage of 300 mg/day.