This study investigated skeletal muscle adaptations to high altitude and a possible role of physical activity levels. Biopsies were obtained from the m. quadriceps femoris (vastus) and m. biceps brachii (biceps) in 15 male subjects, 7 active and 8 less active. Samples were obtained at sea level and after 75 days altitude exposure at 5250 m or higher. The muscle fiber size decreased at an average of 15% in the vastus and biceps, respectively, and to the same extent in both groups. In both muscles, the mean number of capillaries was 2.1-2.2 cap.fiber(-1) before and after the exposure. As mean fiber area was reduced, the mean number of capillaries per unit area increased in all subjects (from 320 to 405 cap/mm2) with no difference between the active and less active groups. The two enzymes selected to reflect mitochondrial capacity, citrate synthase (CS) and 3-hydroxyl-CoA-dehydrogenase (HAD), did not change in the leg muscles with altitude exposure, CS: 28.7 (20.7-37.8) vs. 27.8 (23.8-29.4); HAD: 35.2 (20.3-43.1) vs. 30.6 (20.7-39.7) micromol.min(-1).g(-1) d.w, pre- and post-altitude, respectively. The muscle buffer capacity was elevated in both the vastus; 220 (194-240) vs. 232 (200-277) and the biceps muscles; 233 (190-301) vs. 253 (193-320) after the acclimatization period. In conclusion, mean fiber area was reduced in response to altitude exposure regardless of physical activity which in turn meant that with an unaltered capillary to fiber ratio there was an elevation in capillaries per unit of muscle area. Muscle enzyme activity was unaffected with altitude exposure in both groups, whereas muscle buffer capacity was increased.