Objective: To compare outpatient endometrial sampling cytology with conventional biopsy in postmenopausal women with abnormal uterine bleeding and/or abnormal endometrial thickness at ultrasound. Method: Between December 2003 and December 2009 a group of 1,056 postmenopausal women was referred to the Department of Gynecological Sciences, Perinatology an Child Health II Faculty of Medicine, University of Rome, S.Andrea Hospital. Four hundred and eighty-two patients (45.6%) had abnormal uterine bleeding and 602 (57.0%) showed an endometrial thickness > 5 mm at ultrasound. Patients on hormonal therapy (n = 194) including hormonal replacement therapy (HRT) or tamoxifen (TMX), were enrolled in the study. Endometrial cytologic sampling was performed using a brush device (EBC) while endometrial histological sampling was retrieved using a Novak curette. Histologic evaluation showed: a) malignant neoplasia b) atypical hyperplasia c) benign pathology d) normal or atrophic endometrium. The following points were investigated: a) failure in performing a procedure for cervical stenosis or pelvic pain; b) nondiagnostic specimens; c) diagnostic accuracy. Results: Evidence in score pain differences between brush and curette endometrial samples were observed: 50% of patients undergoing brush cytology had lower pain scores (chi-square = 288.33; p = .001), whereas 60% of patients undergoing endometrial biopsy had higher pain scores (chi-square = 264.84; p = .001). The failure rate in performing procedures was 8.0% vs 4.1%, and the results were statistically significant on the McNemar test, respectively p = .01 and p = .001. A nondiagnostic specimen was obtained in 3.9% of cases by EBC, and 10.3% of cases by the Novak curette (p = .001). Cytological evaluation had a sensitivity of 100%, specificity of 99%, positive and negative predictive value of 97% and 100% for diagnosing malignant neoplasia. Cytology had high diagnostic accuracy for atypical hyperplasia: sensitivity 100%, specificity 99%, positive and negative predictive value 83% and 100%, respectively. Conclusions: EBC is a reliable, well tolerated outpatient diagnostic tool for endometrial sampling in detecting early-stage cancer in postmenopausal patients at high risk for endometrial cancer.