BACKGROUND: The occurrence of low rates of rhabdomyolysis among patients receiving lipid-lowering drugs (LLDs) in randomized clinical trials may be elucidated with population-based studies. OBJECTIVE: To determine the risk of hospitalized rhabdomyolysis associated with LLD therapy. METHODS: This observational study used claims data from 9 million members of five United States health plans to identify patients (≥18 years) who received >2 statin and nonstatin LLDs during July 2000 to December 2004. Inpatient International Classification of Diseases, Ninth Revision, Clinical Modification, codes for rhabdomyolysis (791.3, 728.89, and 728.88) were observed during the follow-up period; cases were confirmed with patients' medical records. Rhabdomyolysis events were reported per 10,000 person-years of LLD exposure; multivariate analysis was conducted. RESULTS: The study cohort (N = 473,343) received 490,988 and 11,624 person-years of LLD, and combination therapy, respectively. Medical charts were obtained for 104 of 144 eligible patients with rhabdomyolysis claims; 42 cases were confirmed. With atorvastatin as reference, rhabdomyolysis rates (95% confidence interval) were greatest for cerivastatin, 8.4 (2.3-21.7); no difference among available statins was observed. Rates for other LLD monotherapies were: niacin, 2.1 (0.3-7.7), ezetimibe, 2.1 (0.3-7.8), fenofibrate, 0 (0-1.7), and gemfibrozil, 2.0 (0.5-5.2). Multivariate analysis showed only cerivastatin with a significantly greater risk of rhabdomyolysis (odds ratio 4.74, 95% confidence interval 1.1-21.2, P = .041) versus atorvastatin among the statins. Combination therapies had increased rhabdomyolysis risk (OR 7.1, 1.6-31.6, P = .010) versus LLDs alone. CONCLUSION: The risk of habdomyolysis among hospitalized patients receiving statins was low; no difference among the available statins was evident. Further data are needed to establish the risk profile but current findings already offer guidance to physicians.