Objectives To compare the quantity and quality of endometrial tissue sampled at saline contrast sonohysterography (SCSH) with that obtained by directed endometrial biopsy by operative hysteroscopy in patients with diffusely thickened and/or inhomogeneous endometrium at SCSH. A secondary aim was a comparison of the extent of procedure-related pain. Methods One hundred and twenty-eight patients with diffusely thickened (> 4 mm) and/or inhomogeneous endometrium at SCSH were prospectively recruited. Endometrial sampling was performed at the end of SCSH using the same 4.7-mm intrauterine catheter that had been used for saline instillation. These samples were compared to directed endometrial biopsies obtained with the guidance of an office S-mm hysteroscope. After hysteroscopy, an extended guided curettage was performed under general anesthesia, providing specimens that were considered the gold standard for histological diagnosis. Endometrial specimen area (mm(2)), histologic concordance and procedure related pain (10-cm VAS) were compared for the two techniques. Results The median age of 88 pre- and of 40 postmenopausal patients was 41 (interquartile range, 34-48) years and 57 (interquartile range, 52-67) years, respectively. The median area of endometrial specimen obtained by SCSH was 25.1 (interquartile range, 12.4-52.3) mm(2) and was not significantly different from that obtained by hysteroscopy (16.9 (interquartile range, 10.0-52.7) mm 2). The K values of the two different techniques for typical hyperplasia (n = 61) and for premalignant and malignant lesions (n = 26) were 0.91 and 0.94, respectively. Procedure-related pain was not significantly different between pre- and postmenopausal patients for both sampling techniques. Conclusions SCSH with sampling proved to be as good as and as tolerable as hysteroscopic biopsy in cases with diffusely thickened and/or inhomogeneous endometrium. Both these imaging and biopsy techniques should be considered a reliable outpatient procedure in the management of patients with abnormal uterine bleeding. Copyright (c) 2007 ISUOG. Published by John Wiley & Sons, Ltd.