We investigated the effects of 14 d of cyclosporine A (CsA) administration on skeletal muscle mitochondrial respiration and submaximal running endurance time in rats. Eight experimental (CsA) and eight control rats followed a 14-d feeding protocol of CsA (20 mg/kg/d) oral administration or placebo. Submaximal endurance exercise time (EET) was measured on a treadmill on Day 13 and mitochondria were isolated from the hind limb muscles homogenate on Day 15. The results showed (1) a significant decrease of EET in CsA versus control rats (29 +/- 8 min versus 60 +/- min, p < 0.001), (2) significantly lower state 3 and uncoupled mitochondrial respiration in CsA compared with control rats with pyruvate plus malate (p < 0.001, p < 0.01) as well as succinate plus rotenone (p < 0.01) as substrates, (3) no differences in coupling efficiency (ADP/O ratios), and (4) significant linear correlation between EET and state 3 respiration (r = 0.71, p < 0.05; r = 0.92, p < 0.001), and strong curvilinear relationship between EET and CsA state 3/mean control state 3 (r2 = 0.81, p < 0.001; r2 = 0.82, p < 0.001), respectively, with pyruvate plus malate and succinate plus rotenone. We conclude that 14 d of CsA oral administration decreases skeletal muscle mitochondrial electron chain capacity without changing coupling efficiency in rats. Results suggest that immunosuppressive therapy is responsible, in part, for poor exercise performance in transplant patients.