OBJECTIVE The clinical relevance of the CYP2D6 oxidation polymorphism in the treatment of depression with desipramine (DMI) was studied prospectively in depressed outpatients. METHODS After CYP2D6 phenotype determination with dextromethorphan, 31 patients were treated with oral DMI at a dosage of 100 mg per day for 3 weeks. At the end of the 3rd week of treatment, severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale and steady-state plasma concentrations of DMI and its metabolite 2-hydroxydesipramine (2-OH-DMI) were measured by high-performance liquid chromatography (HPLC). RESULTS Plasma DMI levels were significantly correlated with dextromethorphan metabolic ratio. The two patients with the poor metabolizer phenotype showed the highest plasma concentrations of DMI and complained of severe adverse effects, requiring dosage reduction. No significant correlation was found between plasma levels of either DMI or DMI plus 2-OH-DMI and antidepressant effect. CONCLUSIONS These findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects. On the other hand, this index of CYP2D6 activity does not seem to predict the degree of clinical amelioration.