Myotoxic effects of 2% lidocaine with 1:100,000 epinephrine were evaluated in rats and humans. Sprague-Dawley rats were give injections in the left gastrocnemius muscle of 0.5 ml of the lidocaine preparation or a control vehicle; they were killed in groups of four at 0, 8, 24, and 48 hours. Blood samples were taken for serum enzyme determinations, and muscle specimens were removed and processed for histologic evaluation. In eight patients undergoing radical neck dissection, 1.8 ml of lidocaine with epinephrine or its control was injected into the sternocleidomastoid muscle approximately 18 hours before surgery. Patients' muscle specimens obtained at surgery were handled similarly to those of the rat. Serum creatine kinase, aspartate aminotransferase, and alanine aminotransferase activities were markedly elevated in the rat at 8 hours in the experimental group, but not in the control group. Histologically, control injections elicited no damage in the rat other than a mild inflammatory reaction along the presumptive needle track. Lidocaine with epinephrine, however, destroyed most of the muscle in which it was injected. Myonecrosis was qualitatively similar in humans. The rat provides a good model for the study of local anesthetic-induced myonecrosis.