1. The incubation of mouse isolated diaphragm with guanidine for 60 min produced ultrastructural changes in the neuromuscular junction, the intramuscular fascicles of the phrenic nerve and the skeletal muscle fibers. 2. The main morphological characteristics of both the end terminals and the nerve fibers were a swollen appearance and an electron-lucent axoplasm. In addition, the mitochondria in these regions were markedly swollen and showed a rarefaction of their cristae as well as a washed aspect of their matrix. Occasional periaxonal vacuoles were present in the myelinated axons. There was a reduction in the number of synaptic vesicles, which was accentuated by the enlarged areas of the majority of the terminals. 3. Muscle cells underwent a range of morphological alterations in the myofibrils and mitochondria. The most drastic type of necrosis affecting these cells was complete dissolution of the myofibrils, which resulted in an apparently empty cell with only the sarcolemma and a few mitochondria remaining intact. 4. Tetrodotoxin was unable to provide total protection against these guanidine-induced changes. 5. We conclude that the ultrastructural effects evoked by guanidine may be associated with modifications in the permeability of the axolemmal and sarcolemmal membranes as a result of changes in ionic conductance. Such ionic disturbances also interfere with the metabolism of mitochondria and the sarcoplasmic reticulum and may account for the well-known inhibitory effect of guanidine on K+ channels and consequently on Ca2+ and Na+ conductances. 6. It is also suggested that the guanidine-induced alterations in the presynaptic and postsynaptic sites could have independent mechanisms of action.30705-11