Skeletal muscle biopsies (vastus lateralis) were performed in 12 patients (mean age 47 +/- 11 years) before and at 3 and 12 months after cardiac transplantation. Fiber type analysis revealed a predominance of type II fibers before cardiac transplantation (66 +/- 10%); the ratio did not change after transplantation. Fiber cross-sectional area increased by 35% to 39% in all fiber types by 12 months after cardiac transplantation. Fiber cross-sectional area, however, remained below the reported normal values. The number of capillaries surrounding each fiber did not change after cardiac transplantation. Skeletal muscle enzyme activity of phosphofructokinase, citrate synthase, and beta-hydroxyacyl coenzyme A dehydrogenase increased by 26%, 47%, and 63%, respectively, after cardiac transplantation (p < 0.05). Peak oxygen uptake also increased significantly after cardiac transplantation (19.5 +/- 8.1 ml/kg/min at 12 months vs 9.8 +/- 1.4 ml/kg/min before transplant, p < 0.01); however, uptake remained 40% below that of predicted. Thus, significant improvement in skeletal muscle morphology and biochemistry occurs in the first year after cardiac transplantation in association with improved exercise capacity. Recovery, however, may be incomplete, which could explain residual impairment of exercise capacity in these patients.