This study tested the hypothesis that exercise in combination with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor produces greater creatine kinase (CK) elevations, an index of skeletal muscle injury, than exercise alone, using a double-blind, placebo-controlled design. Fifty-nine healthy men aged 18 to 65 years with low-density lipoprotein cholesterol (LDL-C) levels greater than 3.36 mmol/L (130 mg/dL) despite diet therapy were studied. Subjects were randomly assigned to receive lovastatin (40 mg/d) or placebo for 5 weeks. Subjects completed 45 minutes of downhill treadmill walking (-15% grade) at 65% of their predetermined maximum heart rate after 4 weeks of treatment. During the subsequent week, they completed four 10-repetition sets of one-arm biceps curl exercise using 50% of their maximum capacity. CK levels were measured before exercise and daily for 4 and 5 days after the treadmill and biceps exercises, respectively. Age, body weight, and blood lipid and lipoprotein levels were similar in lovastatin and placebo groups. Resting CK levels were 33% higher in the lovastatin group before treatment (P < .05), but were not significantly altered by lovastatin. CK levels were 62% and 77% higher (P < .05) in the lovastatin group 24 and 48 hours after treadmill exercise after adjusting for initial CK differences. There were no significant CK differences between lovastatin and placebo groups after biceps curl exercise. We conclude that HMG-CoA reductase inhibitors exacerbate exercise-induced skeletal muscle injury.