Two regimens for infusing vancomycin over 1 h (500 mg every 6 h for five doses or 100 mg every 12 h for three doses) were used in 11 volunteers. Subjects received both regimens one week apart; the regimen used first for each subject was randomized. Nine receiving the 1000-mg dose experienced the "red-man (neck)" syndrome; none had the reaction while receiving the 500-mg dose (P = .002). Plasma histamine concentration, measured every 10 min during the first infusion of each regimen, increased in most subjects given 1000-mg doses; there was only a slight change in histamine levels after 500-mg doses. There was a significant relation between histamine release and reaction severity; frequency and severity of the reaction declined with subsequent doses. We conclude that the red-man syndrome occurs frequently in normal adults who receive 1000 mg of vancomycin over 1 h, that vancomycin causes an infusion rate-dependent increase in plasma histamine concentration, and that the increase in plasma histamine concentration is correlated with the severity of the reaction.