We studied the incidence and type of side effects of minocycline in a double-blind study. A total of 45 volunteers (18 men and 27 women) were given minocycline, and 44 volunteers (23 men and 21 women) were given placebo. The men in both the minocycline and placebo groups were significantly (P < 0.0001) larger than the women in the comparable groups. Minocycline dosage was 100 mg every 12 h for 5 days, and placebo was administered in an identical manner. Minocycline serum concentrations were determined in 12 volunteers at 1, 2, 4, and 6 h after the morning doses on days 1, 3, and 5 of the study. Side effects were recorded by volunteers in diaries and also through daily interviews and were evaluated by examination and electronystagmography. Peak minocycline serum concentrations were seen by day 3 and correlated with the peak onset of side effects. These concentrations were significantly higher in women than in men. Vestibular side effects occurred in 70.4% of the women on minocycline and significantly (P < 0.0001) exceeded the rate of the women on placebo (9.5%). Only loss of balance was significantly (P < 0.05) increased in the men taking minocycline as contrasted with men on placebo. Electronystagmography generally revealed no abnormalities. Side effects were usually not severe: four volunteers in the minocycline group and two in the placebo group discontinued their capsules because of side effects. It is concluded that women experience an unacceptably high incidence of side effects from minocycline, and this may be related to their higher serum concentrations, which in turn may relate to their smaller size.