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Objective The diagnosis of endometrial cancer is made by biopsy sampling with pathological analysis, but it is extremely important to make an accurate diagnosis in order to plan the specific treatment, and we suggest that HE4 in the endometrial tissue and in serum could be tools to make the diagnosis more precise. Material and methods Our prospective study compared patients with endometrial cancer against non-endometrial cancer ones, matched with several variables. The inclusion criteria were females older than 18 years old that accepted to participate in the research study but that had never underwent surgery for other oncological pathologies, whether for ovarian, colon, cervical carcinoma or uterine sarcoma, and none of them had received preoperative chemo or radiotherapy; moreover, they could not have any severe renal or liver pathology. All of them had hysterectomy surgery and the endometrium was studied by a pathologist who compared the regular staining with HE4-antibody staining, in addition, there were collected the serum samples previous to the surgery. Results Suggest bad correlation between the tissue HE4 in patients with and without carcinoma, however, the serum HE4 is statistically significant in the diagnosis of endometrial carcinoma (median EC= 123.1 U, median NE=64.67 U, p=0.002), although the CA125 level is not significant (p=0.208). Conclusion Compared to previous studies our results are quite different in the pathological side, but the serum conclusions are positive and very hopeful as the tumor marker HE4 seems to be able to diagnose endometrial cancer.