Amantadine dose, plasma concentration, prophylactic and adverse effect relationships for prevention of influenza A virus infection in healthy young adult subjects were investigated in a double-blind, placebo-controlled study. Seventy-four subjects with hemagglutination inhibition antibody titers less than or equal to 16 against an attenuated influenza A virus AF9/Montreal/3/72 (H3N2) were randomly allocated to groups taking 0 (placebo), 25, 100, or 150 mg amantadine syrup prophylactically twice a day for 31 doses. Eighteen other subjects were randomly allocated to control groups for investigation of drug toxicity (150 mg) or concurrent other virus infection (placebo). Steady-state trough plasma concentrations were 110 +/- 39, 302 +/- 80, and 572 +/- 207 ng/ml (X +/- SD) for the three amantadine doses and increased out of proportion to dose. Prophylaxis groups were challenged intranasally with virus after the fifth dose at steady state; control subjects received saline solution. No subject became ill. Input virus was recovered 48 or 72 hr after challenge from nose or throat swabs of nine of 21 subjects taking placebo, one of 18 subjects taking 100 mg amantadine, three of 18 subjects taking 25 mg amantadine, and six of 17 subjects taking 150 mg amantadine. There were no differences in seroconversion rates or adverse symptoms. Our data do not support a change in the recommended amantadine prophylactic dose for influenza A virus infection in healthy young adults. We defined trough steady-state plasma concentrations associated with the recommended amantadine dose of 100 mg twice a day that should be mimicked in devising dose schedules for populations with differing amantadine kinetics.