Human epididymis protein 4(HE4) is a secretory glycoprotein found in human distal epididymis epithelial cells. It is often used in the early diagnosis, efficacy evaluation and monitoring of ovarian cancer, and also has been considered as an effective serum marker for many other types of cancer. However, its function in the process of sperm maturation is not fully unknown. The maturation of sperm in epididymis is characterized by the acquisition of motility and fertilization. As a member of the whey acid protein (WAP) family, several studies proposed the importance of HE4 in the maturity of sperm in epididymis. This article reviews the effect of HE4 on spermatozoa maturation in epididymis, which provides basis for the evaluation of male reproductive ability, early detection, early diagnosis and pathogenesis of male infertility.