The use of acetazolamide, a carbonic anhydrase inhibitor, in chronic obstructive pulmonary disease (COPD) remains controversial. A substantial improvement in blood gas values has been documented, with correction of metabolic alkalosis in COPD, in hypoxemic sleep apnea at high altitudes and in acute mountain sickness. This randomized, double-blind study examined the short and long term effects of acetazolamide (2 X 250 mg) on 14 patients with hypoxemia, hypercapnia and metabolic alkalosis (paO2 49 +/- 5.2 mm Hg, paCO2 50 +/- 3.6 mm Hg, base excess + 5.7 +/- 2.3). A crossover between acetazolamide and placebo occurred on days 3, 6 and 9. On day 12 the patients were again randomized and one group further treated with acetazolamide for 4 1/2 (1-7) months. During the short term phase, a significant rise in paO2 to 58 +/- 6.6 mm Hg with acetazolamide was noted, followed by a drop to 53 +/- 5.7 mm Hg with placebo. The paO2 of the five patients on long-term acetazolamide therapy remained unchanged (59 +/- 2.5 mm Hg) while the untreated patients showed a significant drop in paO2 to 46 +/- 8.2 mm Hg. No side effects and no severe metabolic acidosis were noted during acute or long term treatment. Acetazolamide appears to improve hypoxemic and hypercapnic COPD patients with metabolic alkalosis on short and long term therapy.