Epinephrine significantly increases lidocaine-induced skeletal muscle necrosis, even in low concentrations that elicit no damage by themselves. Inasmuch as isoproterenol had no influence on lidocaine myotoxicity, a direct effect of epinephrine on muscle fibers is unlikely. Two vasoconstrictors with dissimilar mechanisms of action, phenylephrine and felypressin, duplicated the potentiating effect of epinephrine on fiber destruction in direct relation to their ability to retard lidocaine absorption from the tissue. It is concluded that the augmentation of muscle necrosis caused by epinephrine is largely due to its ability to increase exposure of skeletal muscle to the local anesthetic.