The study was directed at detecting changes occurring in the early stages of the neurotoxic process induced by an intensive treatment with 2,5-hexanedione. Rats were injected intraperitoneally each day with 450 mg/kg of body weight for the first 14 days and then with 300 mg/kg for an additional 20 days. After 34 days of treatment typical axonal lesions were observed in the sciatic branches, together with electrophysiological signs of denervation in several fibres of the leg muscles. Morphological changes were also found in axons of the spinal cord and optic tracts. At an earlier stage (days 13 to 18), when clinical signs appeared, in the absence of morphological changes in peripheral nerves and of denervated muscle fibres, significant alterations in the functioning of several neuromuscular junctions were observed: increase in frequency and amplitude of miniature end-plate potentials, reduction of the mean quantal content of the evoked end-plate potential (epp) and absence of epp's in some fibres. These changes indicate a progressive functional impairment of nerve terminals which could possibly represent: (a) a primary alteration of the membrane resting and action potentials; (b) a secondary effect of changes in axonal transport. Both these hypothetical events could result from the inhibition of glycolitic enzymes of nervous tissue by 2,5-hexanedione.