BACKGROUND: Muscle effects are the most common reported adverse effects of 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins). However, in placebo-controlled trials the incidence of muscle pain is most often similar for placebo and active control groups. OBJECTIVE: We sought to evaluate whether statin use was associated with a higher prevalence of musculoskeletal pain in a nationally representative sample. METHODS: Cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Participants were 3,580 adults > or =40 years without arthritis who were interviewed at home and examined in a mobile examination center. Participants were asked about sociodemographic characteristics, health conditions, medication use, and musculoskeletal pain. Height, weight, blood pressure, ankle brachial index, and cholesterol were measured. MEASUREMENTS AND MAIN RESULTS: Prevalence and adjusted odds ratios (OR) of any musculoskeletal pain and musculoskeletal pain in 4 different anatomical regions (neck/upper back, upper extremities, lower back, and lower extremities) by statin use during the last 30 days. Among statin users (n = 402), 22.0% (95%CI 18.0-26.7%) reported musculoskeletal pain in at least 1 anatomical region during the last 30 days, compared with 16.7% (95%CI 15.1-18.4%) of those who did not use a statin. Compared to persons who did not use statins, those who used statins had multivariable-adjusted odds ratios (95%CI; p value) of 1.50 (1.07-2.11; p = .01) for any musculoskeletal pain, 1.59 (1.04-2.44, p = .03) for lower back pain, and 1.50 (1.02-2.22, p = .03) for lower extremity pain. CONCLUSION: Musculoskeletal pain is common in adults > or =40 years without arthritis. In this nationally representative sample, statin users were significantly more likely to report musculoskeletal pain.