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Background. In a prospective study, the differential diagnostic potential of pelvic examination, ultrasound, and serum CA 125 assay in postmenopausal patients presenting with a pelvic mass was assessed. Methods. A total of 228 patients were evaluated preoperatively in an international, multicenter, prospective study using a standard protocol for pelvic examination, transvaginal (occasionally additional abdominal) ultrasound, and serum CA 125 determination with a cut-off level of 35 U/ml. Results. Ninety-five malignant (41.7%) and 127 benign (55.7%) pelvic tumors were found in addition to 6 borderline ovarian tumors (2.6%) in the 228 patients. Seventy-two patients had ovarian carcinoma, 49 of whom were International Federation of Gynecology and Obstetrics Stage III or IV. Borderline tumors were excluded from the statistical calculations. The individual accuracy of pelvic examination, ultrasound, and serum CA 125 in discriminating between benign and malignant pelvic masses was approximately the same (76, 74, and 77%, respectively). Using logistic regression analysis, the power of pelvic examination appeared to be the most relevant factor (adjusted odds ratio, 9.2), followed by serum CA 125 (odds ratio, 5.6), and ultrasound (odds ratio, 4.9). Age appeared to be nonpredictive. No cancer was found in any patient in whom all three methods scored negative (n = 53; positive predictive value for malignancy = 0 and 95%; confidence interval, 0-7). Conclusions. The combined use of pelvic examination, ultrasound, and serum CA 125 leads to improved discrimination between malignant and benign pelvic masses, because malignancy can be excluded when all three examination methods are negative. A change to a more patient-tailored surgical approach could be considered in those cases. Cancer 1994; 74:1398-1406.