Although an inotropic effect of digitalis on skeletal muscle has been demonstrated in animals, it has not been shown in man. Digitalis, in previous studies, has failed to improve voluntary exercise performance. In this investigation the strength of nerve-stimulated involuntary thumb adduction was measured before, during and after infusion of ouabain into the brachial artery. With this experimental design, the many uncontrolled factors that govern ordinary exercise tolerance were avoided. Large doses of ouabain (0.5 mg) produced significant augmentation of peak strength of thumb adduction whereas smaller doses (75 mug) more likely to reach the thumb during systemic digitalization produced only suggestive increases in peak contraction strength. In patients previously digitalized for heart failure, the large doses of ouabain did not significantly change contractility. The findings suggest that skeletal muscle is less sensitive than cardiac muscle to ouabain, and that systemic digitalization has a minor effect on skeletal muscle. When the differences between skeletal and cardiac muscle in excitation-contraction coupling are considered, the reduced effect of ouabain on skeletal muscle contraction is compatible with cell membrane locus of action in both tissues.