Six healthy volunteers each received imipramine on four occasions in random sequence, i.v. (12.5 mg) and p.o. (50 mg) in a drug-free state and i.v. and p.o. while taking cimetidine 300 mg every 6 hr. After i.v. doses, elimination half-life of imipramine was increased during cimetidine treatment (22.1 vs. 15.5 hr, P less than .02) as a result of decreased total metabolic clearance (623 vs. 1048 ml/min, P less than .05) with no change in volume of distribution (17.2 vs. 19.8 liters/kg) or plasma protein binding (unbound percent, 17.7 vs. 16.5%). After single p.o. imipramine doses, peak imipramine blood levels achieved were greater during cimetidine therapy (34.4 vs. 19.3 ng/ml, P less than .05) and area under the time/concentration curve was greatly increased (569 vs. 306 ng/ml X hr, P less than .05). Desipramine, the biologically active metabolite of imipramine, was measurable only after p.o. doses. Desipramine area under the time/concentration curve was increased during cimetidine therapy after p.o. imipramine doses (274 vs. 152 ng/ml X hr, P less than .05), suggesting that desipramine clearance was inhibited as well. Comparison of i.v. and p.o. imipramine doses indicated absolute bioavailability was 40.2% in the control state and increased to 75.3% (P less than .05) during cimetidine treatment. Imipramine, with both impaired total metabolic clearance and enhanced bioavailability, in conjunction with increased accumulation of desipramine, would have marked increases in steady-state plasma concentration of both imipramine and desipramine with concurrent cimetidine therapy during chronic p.o. treatment.