The effect of oleamide on apoptosis was investigated by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction assay, DNA staining assay with propidiumiodide and caspase-3 activity analyses. The present results showed that oleamide significantly attenuated the cell death and nuclear condensation of cultured rat cerebellar granule neurons induced by K+ deprivation in a dose-dependent manner. The oleamide actions were well parallel with the attenuation of caspase-3 activity in the process of apoptotic death. Moreover, neither elaidic acid nor stearic acid, two fatty acids structurally related to oleamide without the Δ9-cis double bond, had similar effects on the cell death, suggesting the selectively structural features of oleamide required for this action. These data provided the first evidence of a protective effect of oleamide against apoptosis in a structurally specific manner.