1. The aim of this study was to examine the effect of muscle pH on muscle metabolism and development of fatigue during intense exercise. 2. Seven subjects performed intense exhaustive leg exercise on two occasions: with and without preceding intense intermittent arm exercise leading to high or moderate (control) blood lactate concentrations (HL and C, respectively). Prior to and immediately after each exercise bout, a muscle biopsy was taken from m. vastus lateralis of the active leg. Leg blood flow was measured and femoral arterial and venous blood samples were collected before and frequently during the exhaustive exercises. 3. The duration of the exercise was shorter in HL than in C (3.46 +/- 0.28 vs. 4.67 +/- 0.55 min; means +/- S.E.M.; P < 0.05). Before exercise muscle pH was the same in C and HL (7.17 vs. 7.10), but at the end of exercise muscle pH was lower in HL than in C (6.82 vs. 6.65; P < 0.05). The release of potassium during exercise was higher (P < 0.05) in HL compared with C, but the arterial and femoral venous plasma potassium concentrations were the same at exhaustion in HL and C. 4. Muscle lactate concentration was higher in HL compared with C (3.7 +/- 0.4 vs. 1.6 +/- 0.2 mmol (kg wet weight)-1; P < 0.05), but the same at exhaustion (26.5 +/- 2.7 vs. 25.4 +/- 2.4 mmol (kg wet weight)-1). Total release of lactate in HL was lower than in C (18.7 +/- 4.5 vs. 50.4 +/- 11.0 mmol; P < 0.05), but rate of lactate production was not different (9.0 +/- 1.0 vs. 10.2 +/- 1.3 mmol (kg wet weight)-1 min-1). The rate of muscle glycogen breakdown was the same in C and HL (8.1 +/- 1.2 vs. 8.2 +/- 1.0 mmol (kg wet weight)-1 min-1). 5. The present data suggest that elevated muscle acidity does not reduce muscle glycogenolysis/glycolysis and is not the only cause of fatigue during intense exercise in man. Instead, accumulation of potassium in muscle interstitium may be an important factor in the development of fatigue.