Decreased ventilatory responses to carbon dioxide (CO2) correlate with elevated scores on tests for depression in normal subjects and with episodes of endogenous depression in psychiatric patients. Patients with severe chronic obstructive pulmonary disease (COPD) frequently develop resting hypercapnia due to impaired ventilatory mechanics or drive, and may also have elevated scores on tests for depression. Tricyclic antidepressant drugs can improve ventilatory mechanics and possibly drive. We hypothesized that antidepressant drugs might enhance ventilatory drive and improve arterial blood gases in patients with severe COPD and that these improvements might correlate with improvement in depression scores. Therefore, we studied the effects of desipramine versus placebo on spirometry, resting arterial blood gases, hypercapnic ventilatory and mouth occlusion pressure responses, and scores on the Beck and Zung self-rated depression scales. In our patients the resting arterial CO2 (PaCO2) was found to depend almost equally on ventilatory mechanics and drive. In addition, patients with higher depression scores tended to have a lower PaCO2 when the severity of airways obstruction was taken into consideration. In a 16-week, double-blind, crossover comparison of desipramine with placebo, both treatments led to significant improvement in depression scores. Desipramine had no effects on resting PaCO2, spirometry, or ventilatory control.