The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.