Cimetidine has been shown to inhibit the oxidative metabolism of a variety of low- and high-extraction drugs. Despite the findings of initial investigators, there is evidence that ranitidine may exert similar effects. Eight healthy volunteer subjects took part in a within-subject crossover study. They received midazolam, 15 mg, by mouth after pretreatment with cimetidine, ranitidine, or nothing and midazolam, 10 mg, intravenously on separate occasions. Mean absolute bioavailability of midazolam was increased by more than 30% after cimetidine (P less than 0.01) and 26% after ranitidine (P less than 0.05). The data, which agree with a concurrent clinical study indicating greater hypnotic action of midazolam after ranitidine, indicate that this is not a result of enhanced midazolam absorption and that reduced hepatic clearance is the most likely explanation.