The main aims of this study were to determine the expression of human epididymis protein 4 (HE4) in endometrial cancer and to explore the relationships between HE4 expression, clinicopathological parameters, and prognosis. Immunohistochemistry was used to detect HE4 expression in 102 cases of endometrial cancer, 30 cases of endometrial atypical hyperplasia, and 20 cases of normal endometrium. The positive expression rate of HE4 in endometrial carcinoma was 84.62%, significantly higher than 66.67% in atypical hyperplasia (P < 0.05) and 15.00% in normal endometrium (P < 0.0.01). With the exception of stage II, HE4 expression in endometrial cancer showed an increasing tendency with increased clinical stage (P < 0.05). The positive expression rate of HE4 increased with a decrease in the degree of differentiation. A statistically significant difference was observed between the highly differentiated group and the poorly differentiated group (P < 0.05). Mortality in endometrial cancer patients with high HE4 expression was significantly higher than that in patients with low HE4 expression (P < 0.05). Endometrial cancer patients with high HE4 expression have a poor prognosis.