AbstractAim: Although CA125 is the most widely used cancer marker in the diagnostic approach of pelvic masses in women, its clinical usefulness is limited because it lacks expression of the antigen in the early stages of disease. The human epididymis protein 4 (HE4) is frequently over‐expressed in ovarian cancer, whereas its expression in normal tissues, including the ovary, is low. The aim of this study was to assess the concentration of both HE4 and CA125 in patients with different forms of benign and malign pelvic masses.Methods: The study population included 99 patients with gynecological cancer (46 ovarian, 39 endometrial, 14 cervical) and 40 affected by benign disease (22 endometriosis and 18 benign ovarian mass). Twelve control subjects were also included in the study. In all the patients, serumsamples were collected on the day before scheduled surgery.Results: The median CA125 and HE4 serum levels were significantly higher among ovarian cancer patients as compared with healthy subjects and with those with benign mass, cervical, and endometrial tumors. The receiver operating characteristics curve analysis on healthy controls and patients with ovarian cancers revealed that HE4 had a significantly higher area under the curve when compared with CA125 (0.99 vs. 0.91), with a sensibility and specificity of 98 and 100%, respectively.Conclusions: HE4 seems to be a promising ovarian cancer marker, and its measurement might improve the diagnostic approach to patients with pelvic masses. J. Clin. Lab. Anal. 23:331–335, 2009. © 2009 Wiley‐Liss, Inc.