The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50–150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges.