To assess whether acetazolamide (Az), used prophylactically for acute mountain sickness (AMS), alters exercise capacity at high altitude.Az (500 mg daily) or placebo was administered to 20 healthy adults (aged 36±20 years, range 21-77), who were paired for age, sex, AMS susceptibility and weight, in a double-blind, randomised manner. Participants ascended over 5 days to 4559 m, then exercised to exhaustion on a bicycle ergometer, while recording breath-by-breath gas measurements. Comparisons between groups and matched pairs were done via Mann-Whitney U and Pearson's χ2 tests, respectively.Comparing paired individuals at altitude, those on Az had greater reductions in maximum power output (Pmax) as a percentage of sea-level values (65±14.1 vs 76.6±7.4 (placebo); P=0.007), lower VO2max (20.7±5.2 vs 24.6±5.1 mL/kg/min; P<0.01), smaller changes from rest to Pmax for VO2 (9.8±6.2 vs 13.8±4.9 mL/kg/min; P=0.04) and lower heart rate at Pmax (154±25 vs 167±16, P<0.01) compared with their placebo-treated partners. Correlational analysis (Pearson's) indicated that with increasing age Pmax (r=-0.83: P<0.005) and heart rate at Pmax (r=-0.71, P=0.01) reduced more in those taking Az.Maximum exercise performance at altitude was reduced more in subjects taking Az compared with placebo, particularly in older individuals. The age-related effect may reflect higher tissue concentrations of Az due to reduced renal excretion. Future studies should explore the effectiveness of smaller Az doses (eg, 250 mg daily or less) in older individuals to optimise the altitude-Az-exercise relationships.