Statins, among the most commonly prescribed medications, are associated with a wide range of musculoskeletal side effects. These include a progressive autoimmune myopathy with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies that requires immunosuppression. However, it remains unknown whether these antibodies are found in statin users with and without self-limited musculoskeletal side effects; this limits their diagnostic utility. The current work assessed the prevalence of anti-HMGCR antibodies in these groups of statin users. We determined the prevalence of anti-HMGCR antibodies in 1,966 participants (including 763 current statin users) in a substudy of the community-based Atherosclerosis Risk in Communities (ARIC) Study and 98 French Canadian subjects with familial hypercholesterolemia, including 51 with documented statin intolerance. No participant in the ARIC substudy, including those with past or current statin exposure at the time of sample collection, had anti-HMGCR antibodies. Similarly, none of 51 patients with self-limited statin intolerance or 47 statin-tolerant patients receiving maximal statin therapy were anti-HMGCR positive. The majority of patients with and without statin exposure, including those with self-limited statin intolerance, do not develop anti-HMGCR antibodies. Therefore, anti-HMGCR antibodies are highly specific for those with an autoimmune myopathy.