Pretreatment of rats with atropine and the reversible esterase inhibitor physostigmine [-)PHY), prior to injection of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg), protects 100% of the animals from lethality. We have used quantitative light and qualitative electron microscopy to show that damage to the end plate region of voluntary muscles is also strikingly limited by the same pretreatment. Drug effects on soleus motor end plates detectable 1 hr after treatment were (1) a single sublethal dose of sarin (0.08 mg/kg) produced large, blistered, and severely disrupted subjucntional regions. Damage extended from the end plate, in the form of myofiber necrosis and subsequent phagocytosis; (2) (-)PHY (0.1 mg/kg) itself had a selective effect in inducing irregularities of the subjunctional sarcomere band without any gross vacuolization; (3) the morphometric analysis done with light microscopy indicated that the combination of atropine (0.5 mg/kg) and (-)PHY (0.1 mg/kg) prior to a lethal dose of sarin (0.13 mg/kg) offered 86% reduction in the average area of the lesions, relative to the dimensions of damage induced by atropine/sarin alone. In most lesions induced by (-)PHY, recognizable changes were markedly less severe in degree and extent than those seen in sarin myopathy; there were few instances of extensive muscle damage and myofiber necrosis. The relationship of the (-)PHY dose to the level of protection against sarin suggested that (-)PHY pretreatment almost completely prevents the characteristic sarin-induced myopathy and, instead, imposes the characteristic PHY-induced subjunctional swelling. In all three experimental groups examined, the myopathic changes located extrajuctionally were reversible. The mechanism by which (-)PHY acts as a protective agent is discussed.