The mechanism of the muscle toxicity associated with lipid-lowering therapy remains obscure. Pathological and biochemical findings in patients with statin myotoxicity suggest impaired fatty acid oxidation. Exhaled gas analysis can be used to assess substrate utilization including fatty acid oxidation. In order to determine if muscle toxicity due to lipid-lowering therapy might be related to abnormalities in lipid oxidation, exhaled gas analysis was performed in the fasted state on 11 patients subsequent to statin-associated myositis reactions. Results were compared to those of 16 normal controls who were measured both on and off statin therapy. Post-myositis patients showed a depressed anaerobic threshold (AT) (P=0.009) compared to controls while age-adjusted maximal oxygen consumption (VO2max) and ventilatory efficiency (VE/VCO2) were not significantly different. The fasting respiratory exchange ratio (RER) of post-myositis patients off statins was abnormally increased (P=0.00001) as was their S1-slope (P=0.023). Controls demonstrated a significant increase in their RER while taking statins consistent with decreased lipid oxidation (P <0.00001). These findings suggest that abnormal lipid oxidation in certain patients may predispose them to the myotoxicity caused by lipid-lowering therapies.