Morphine has been proposed as a treatment for breathlessness in patients with severe chronic obstructive pulmonary disease (COPD), but there is uncertainty as to whether or not it is effective. Orally administered sustained-release morphine was compared with placebo in a randomized, double-blind, crossover trial with two 6-wk treatment periods separated by a 2-wk washout period. The primary end point was quality of life measured using the Chronic Respiratory Disease Questionnaire (CRQ). Secondary end points included 6-min walk (6MW), distance, and breathlessness scores. Sixteen subjects with a mean age 70.7 yr, FEV1 of 0.6 L, and VC of 1.90 L were studied. There was no change in the total CRQ score with either treatment, but the score on the Mastery subscale was significantly worse with morphine (p = 0.02). The 6MW distance increased by 21 m from the beginning to the end of the placebo treatment period, but it decreased by 35 m with morphine (p = 0.04). There were no differences between treatments in breathlessness scored on daily diary cards or on the Dyspnea subscale of the CRQ. Almost all the subjects experienced adverse effects related to morphine. Sustained-release morphine was not a useful treatment for breathlessness in these patients with severe COPD.