During each of two six-week treatment periods, 12 depressed outpatients with chronic obstructive pulmonary disease received increasing doses of doxepin hydrochloride or a placebo as tolerated. The mean maximal doses of doxepin hydrochloride and placebo were 105 and 128 mg, respectively. Three of the 12 patients dropped out because of doxepin's side effects. The depression and anxiety scores at the end of the treatment periods were virtually identical and not significantly different from baseline scores. Changes in the 12-minute walking distance were more closely correlated with changes in the depression and anxiety scores than with changes in the forced expiratory volume in 1 s or forced vital capacity. Thus, doxepin is ineffective in treating depressed patients with chronic obstructive pulmonary disease; improvements in the 12-minute walking distance were closely correlated with improvements in the depression or anxiety scores.