Psychiatric disorders occur frequently in patients with COPD, but therapy with psychotropic drugs is often limited by concomitant depression of ventilatory drive. We present a patient with COPD and major depression who developed hypercapnic respiratory failure while receiving nortriptyline and oxazepam. Because of known respiratory depressant effects of the latter drug, nortriptyline alone was resumed upon recovery. Depression of CO2 sensitivity and ventilatory load compensation with a concomitant increase in exercise tolerance with decreased dyspnea was observed while she was receiving nortriptyline. These results demonstrate a previously unreported depressant effect of nortriptyline on ventilatory control, and they suggest the need for further investigation of the ventilatory effects of this drug in patients with pulmonary disease.