Experiments were performed to elucidate the mechanism of action by which the oxime HI-6 causes a recovery of neuromuscular function after oxime-resistant inhibition of acetylcholinesterase by the organophosphate S27. In the presence of HI-6 (1-3 mM), the ability of isolated rat diaphragm muscle strips to sustain tetanic contractions after inhibition by S27 was markedly improved, as was the electrophysiological response to indirect tetanic stimulation. At lower concentrations (0-1 mM), HI-6 reduced the amplitude of the miniature endplate potentials and their decay time constant in a dose-dependent manner without having any effect on the resting membrane potential. In addition, HI-6 dose dependently increased the quantal content. It is likely that these post- and presynaptic effects of HI-6 are responsible for the improvement of muscle contractions after inhibition of acetylcholinesterase and they could well be of value in the therapy of organophosphate poisoning.