The two structurally similar tricyclic antidepressant drugs amitriptyline (AT) and chlorimipramine (CI) were administered to 15 patients in a cross-over study. Approximately equimolar daily doses of the two drugs (5 mumol/kg body weight) were given as commercial tablets. Steady state plasma levels of the parent drugs and the demethyl metabolites were determined by high performance liquid chromatography. An about 5-fold interindividual variation was found in plasma levels of all four compounds. As the reciprocal plasma level during multiple dosing is proportional to the clearance of a compound, this parameter was used for linear regression analysis. In the 15 patients there was a significant correlation between the reciprocal plasma levels of CI and its metabolite demethylchlorimipramine (r = 0.76; p less than 0.001) and also between AT and its metabolite nortriptyline (r = 0.52; p less than 0.05). The reciprocal plasma levels of the parent compounds AT and CI were closely correlated (r = 0.87; p less than 0.001). A similar correlation was found for the demethyl metabolites (r = 0.77; p less than 0.001). The results indicate that similar factors control the plasma levels of AT and CI during treatment and that similar enzymes may be involved in the metabolism of the two drugs.