Interaction between azithromycin and midazolam was investigated in a double-blind, randomized crossover study of 2 phases. Ten healthy volunteers were given azithromycin (500 mg on day 1 and 250 mg on days 2-5) or placebo pretreatments. On day 5 they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h. Azithromycin treatment increased the median (range) concentration peak time of midazolam from 1.0 (0.5-2) h to 1.25 (0.5-5) h and decreased plasma concentrations of midazolam during initial 3 hours after the intake of midazolam (p < 0.05). Mean +/- SE mean peak concentration of midazolam was decreased from 86 +/- 17 ng ml-1 to 57 +/- 9 ng ml-1 (p < 0.05). Azithromycin did neither increase the total area under concentration-time curve nor change the elimination half-life of midazolam. In Maddox wing test the maximum effects of midazolam were reached later during azithromycin phase, but no other changes were observed in pharmacodynamics of midazolam. Azithromycin may delay the absorption of midazolam, which can postpone the onset of action of midazolam.