Obesity is caused by a chronic positive energy balance, which not only increases the amount of lipid in adipose tissue, but also, in non-adipose tissue. Excessive accumulation of lipids in tissues may lead to cell dysfunction or cell death, a phenomenon known as lipotoxicity. The aim of this study was to investigate the effects of high-fat diet (HFD) feeding on the sciatic nerves of both male and female mice. HFD feeding induced increased mRNA levels of Bax and Bcl2 in HFD group of males only, although the accumulation of fatty acids in the sciatic nerves was induced by HFD feeding in the both sexes. To determine whether estrogen was involved in the inhibitory effects of HFD feeding-induced increased expression of apoptosis-related genes, ovariectomized (OVX) females were fed a normal diet (ND) or HFD with or without daily ethinylestradiol treatment for 1 week. In OVX mice, the mRNA levels of Bax and Bcl2 in HFD group were higher than in ND group. In contrast, in OVX mice treated with ethinylestradiol, there was no significant between ND and HFD groups. In conclusion, HFD induced apoptosis in the sciatic nerves of males, but not females, and estrogen had inhibitory effects on HFD-induced apoptosis in the sciatic nerves of females. Long-term feeding studies are needed to investigate the pathological effects on sciatic nerves of mice fed HFD as pathological findings were not observed under our study condition.