Statin therapy is associated with muscle problems in approximately 10% to 25% of patients treated in clinical practice, but muscle problems have rarely been reported in controlled clinical trials. We performed a systematic search and review of statin clinical trials to examine how these studies evaluated muscle problems and to determine why there are apparent differences in muscle problems between clinical trials and practice. We initially identified 1,012 reports related to clinical trials of statin therapy, 42 of which qualified for analysis. Fifteen, 4, and 22 trials reported creatine kinase values only >10, 5, and 3 times the upper limits of normal, respectively, in both statin- and placebo-treated participants. Four trials reported average creatine kinase values, which increased with statin treatment in 3 instances. Twenty-six trials reported muscle problems, with an average incidence in statin- and placebo-treated participants of 13%, but only one trial specifically queried about muscle problems. Three trials used a run-in period to eliminate participants with statin intolerance and noncompliance. The percentage of muscle problems tended to be higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06). This small difference probably reflects a high background rate of nonspecific muscle problems in both groups that could not be distinguished from statin-associated myalgia because most clinical trials did not use a standard definition for statin myalgia.