Daily injection of guanidine, which enhances the release of acetylcholine, rapidly produces a severe myopathy in the soleus muscle of the Sprague-Dawley rat. The myopathy is inhibited by prior sciatic nerve section and is accentuated by cholinesterase inhibition. Carbamylcholine, an acetylcholine analogue that depolarizes the end-plate and causes contraction, does not induce myopathy in rats when given in almost lethal doses. These results suggest that excessive acetylcholine can induce skeletal muscle necrosis even when the cholinesterase system is intact. The myopathy is not just the result of excessive depolarization and contraction but more likely is related to a disturbance in the trophic effect mediated by acetylcholine.