In patients with congestive heart failure (CHF), exercise limitation correlates poorly with central hemodynamic abnormalities, suggesting that additional abnormalities in skeletal muscle blood flow or metabolism play an important pathophysiologic role. Therefore, muscle metabolism was examined by 31P nuclear magnetic resonance (NMR) at rest and during repetitive bulb squeeze exercise in 11 patients with New York Heart Association class II to IV CHF and 7 age-matched control subjects. Serial spectra were obtained at rest, at 2 levels of exercise and during recovery. At rest, the only abnormal finding was an elevated inorganic phosphate (P i) concentration (5.0 ± 1.5 vs 3.6 ± 0.4 m M, p < 0.01). At the lower exercise level, phosphocreatine (PCr) utilization, which was followed as the ratio of [PCr] ([PCr] + [P i]) , was greater (0.36 ± 0.16 vs 0.53 ± 0.10, p < 0.02), and pH fell more rapidly and to a lower value (6.38 ± 0.25 vs 6.85 ± 0.17, p < 0.001). At the higher level of exercise, the patients could not work effectively and the group differences narrowed. Compared with control subjects, acidification was disproportionately greater in relation to PCr depletion in patients, further suggesting excessive dependence on glycolytic metabolism. The P i peak was prominently double in 5 patients, indicating presence of a population of muscle fibers undergoing unusually active glycolysis. PCr resynthesis, a reflection of oxidative phosphorylation, was delayed in 4 patients. These findings indicate that in many patients with CHF, exercising muscle has marked metabolic changes consistent with impaired substrate availability and altered biochemistry.