Purpose: The objective of this study was to evaluate the effect of tamoxifen on the endometrium of 45 postmenopausal women with breast cancer, as evidenced by hysteroscopic, ultrasound, histological methods, and by immunohistochemical investigation of the expression of Bcl-2 and Ki67. Materials and Methods: Forty-five postmenopausal women with breast cancer (ER and/or PgR positive) undergoing tamoxifen therapy for six to 48 months, were selected from the files of the 2nd Department of Obstetrics and Gynecology, University of Athens Aretaieion Hospital, among a total of 120 patients treated from 2004-2009. Results: The ultrasound findings during the follow-up period revealed 18 cases of thickened endometrium, 14 cases of suspected polyps, one case with accumulation of endometrial fluid, and 12 cases of heterogeneous endometrial echo texture. The patients had undergone hysteroscopy because of thickened endometrium (18/45 patients), postmenopausal bleeding (14/45 patients), and polyps (13/45 patients). The endometrial tissue samples were examined in the Pathology Department of Aretaieion Hospital and showed in 23 cases with adenomatous endometrial polyps, 15 cases with endometrial cystic atrophy, two cases with adenomatous hyperplasia, and five cases with mucosal endometrial adhesions. Immunohistochemical investigation of Bcl-2 and KJ67 expression was undertaken on paraffin blocks and showed elevated expression in the cases with endometrial polyps and hyperplasia, in contrast to atrophic endometria. Conclusion: Long-term tamoxifen therapy of postmenopausal women with breast cancer is associated with uterine pathology. Ultrasonography alone is useful in asymptomatic patients selecting cases with increased endometrial thickness for further investigation. Hysteroscopy is an accurate method for diagnosing endometrial disease because it provides a direct view of the uterine cavity, reveals focal lesions, and enables targeted biopsies to be performed at the same time. Pathological findings show elevated expression of Ki67 and Bcl-2 in hyperplastic endometria and adenomatous polyps, consistent with an elevated glandular cell proliferation due to tamoxifen effect.