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To determine if alterations in muscle morphology occur after subchronic oral administration of pyridostigmine bromide, rats were fed 90 mg/kg continuously in meal and examined at 1, 2, 4, 7, and 15 days. Within the first day, cholinesterase activity was reduced by 87% and remained inhibited by 74-91% for the entire course of the feeding. Light microscopy demonstrated that by the first day approximately 1 in 100 myofibers was shrunken and contained centralized nuclei. Electron microscopic examination showed that while presynaptic areas of neuromuscular junctions were relatively unaffected by this dose, postsynaptic areas invariably showed maximal changes. Ultrastructural alterations included disruption of myofilaments, mitochondrial changes consistent with accumulation of calcium, and nuclear alterations. These effects appeared not to be cumulative and were greatly diminished by 15 days even under constant drug administration and inhibition of cholinesterase activity. We conclude that subchronic feeding of pyridostigmine bromide induces primarily myopathic rather than neurogenic changes in the diaphragm and that some mechanism of accommodation may be activated that minimizes continued muscle injury.