3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are commonly used for treatment of hyperlipidemia and its deleterious effects. Myotoxicity has been associated with use of these agents. We report two cases of inflammatory myopathy in patients receiving these agents that did not respond to drug withdrawal and required immunosuppressive treatment. One of these patients developed an antibody to histidyl tRNA synthetase or Jo-1, an autoantibody associated with idiopathic inflammatory myopathies. We suggest that HMG-CoA reductase inhibitor-associated myotoxicity may trigger an immune-mediated inflammatory myopathy. Patients whose muscle abnormalities do not resolve with drug withdrawal should be considered for muscle biopsy.