The percutaneous absorption of amitriptyline, nortriptyline, imipramine, and desipramine as their hydrochloride salts in vivo was demonstrated without use of a vehicle using the hairless (hr-1/hr-1) mouse as an experimental model for human skin. After topical application of 2 mg of each compound in distilled water, followed by rapid evaporation of the water, concentrations were measured in heart, lung, brain, liver, and blood in 1-, 2-, 4-, and 6-hour study groups. Lung consistently demonstrated the highest concentrations for all four compounds while heart and liver had the lowest. Concentrations in heart remained essentially constant for all compounds during the 6-hour study period. The concentrations in solid tissues were much lower than those commonly seen in man after overdose, whereas the concentrations in blood resembled low therapeutic to toxic concentrations in humans. Percutaneous absorption may provide a feasible route of administration for the tricyclic antidepressants which may lead to improved compliance with fewer gastrointestinal side effects.