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The aim of this retrospective cross-sectional study was to assess the usefulness of phosphase and tensin homolog deleted on chromosome 10 (PTEN) and p53 protein immunoexpression in predicting the risk of malignancy in endometrial polyps. The study was conducted at tertiary public hospital, university teaching center, and private practice clinic.A total of 159 patients with endometrial polyps who underwent hysteroscopic polypectomy between January 2010 to December 2014 were included. p53 and PTEN immunoexpression were assessed in histologic endometrial polyp samples. Patients were allocated into 2 groups: group A, endometrial polyps without atypia (120), and group B, endometrial polyps with atypia (39), which were subdivided into A1 (80) and B1 (21) = p53−/PTEN+ immunostaining; A2 (20) and B2 (11) = p53+/PTEN+; A3 (14) and B3 (4) = p53+/PTEN−; A4 (6) and B4 (3) = p53−/PTEN−.There was no significant difference between groups regarding clinical and epidemiologic parameters, except for age. Neoplasia incidence within groups was higher when at least 1 marker was abnormally stained (in group A, P = .0089, odds ratio [OR] = 13.94 [1.62; 120.27]; in group B, P = .0255, OR 12.73 [1.38; 117.27]). Overall neoplasia incidence was higher in group B than in group A (20.5% vs 5.8%; P = .0113). Malignant neoplasia was found more frequently in patients with p53+ (P = .0006, OR = 7.67 [2.30; 25.54]) and PTEN− (P = .0043; OR = 5.43 [1.77; 16.61]).Immunohistochemical analysis using p53 and PTEN as markers, either alone or concomitantly, can be useful to predict malignant transformation in cases of endometrial polyps.