Influence of oxidative stress on fusion of pre-synaptic plasma membranes with phosphatidylcholine (PC) liposomes as a model of synaptic vesicle was investigated. The inhibitory effect of vitamin E on the decline in the fusion caused by oxidative stress was also assessed. Rats subjected to hyperoxia as oxidative stress showed significant increases in the levels of lipid hydroperoxides and protein carbonyl moieties in pre-synaptic plasma membranes in the brain. The ζ potential of pre-synaptic membrane surface was decreased markedly. When synaptosomes were incubated with PC liposomes labeled by either rhodamine B or calcein as a fluorescence probe, or 12-doxyl stearic acid as an ESR spin trapping agent, translocation of each probe into oxidatively damaged pre-synaptic membranes was decreased significantly. Fatty acid composition analysis in pre-synaptic membranes obtained from normal rats revealed a marked increase in linoleic acid and a moderate decrease in docosahexaenoic content after the incubation with liposomes. However, rats subjected to hyperoxia did not show marked changes in these fatty acid contents in their pre-synaptic membranes after the incubation. Such changes caused by hyperoxia were inhibited by vitamin E treatment of rats. These results suggest that oxidative damage of pre-synaptic membranes caused by oxidative stress lowers the lipid-mixing for the membrane fusion. The results of this study imply that vitamin E prevents the deficit in neurotransmission at nerve terminals due to the decline in fusion between pre-synaptic membrane and synaptic vesicles caused by oxidative membrane damage.