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Objective: To evaluate prospectively whether saline-infusion sonography endometrial sampling will improve diagnosis of benign and malignant endometrial disease compared with blind endometrial biopsy in perimenopausal and postmenopausal women with abnormal uterine bleeding., Methods: After initial assessments and endometrial biopsies, women aged 40 or older with abnormal uterine bleeding were referred for transvaginal ultrasonography. Patients with abnormal endometrial evaluations were offered sonohysterography and invited to enter the saline-infusion sonography endometrial sampling study. Saline-infusion sonography endometrial sampling was performed at the end of sonohysterography using an endometrial sampling curette at the sight of the endometrial abnormality or at a representative site in the endometrial cavity if the cavity was normal. Histopathologic diagnoses of blind endometrial biopsy and saline-infusion sonography endometrial sampling were compared with final outcomes. Kappa values for the two sampling techniques were calculated for diagnostic accuracy., Results: A total of 88 saline-infusion sonography endometrial samples were obtained; final outcomes were attained in 80 cases. When comparing saline-infusion sonography endometrial sampling with final outcomes, saline-infusion sonography endometrial sampling provided a diagnosis 89% of the time (95% confidence interval [CI] 82-95%) compared with endometrial biopsy at 52% (95% CI 42-62%). Forty-five patients with endometrial biopsies had final outcomes. When comparing endometrial biopsy with final outcomes, endometrial biopsy underestimated the incidence of pathology, especially when focal lesions and malignancy were present. This difference was statistically significant (P<.005)., Conclusion: Saline-infusion sonography endometrial sampling is superior to endometrial biopsy in diagnosing endometrial pathology in perimenopausal and postmenopausal women with abnormal uterine bleeding., Level of Evidence: II.