OBJECTIVE: We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. STUDY DESIGN: Patients were recruited in 2 related prospective, multiinstitutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. RESULTS: A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primarystage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies,MIAcombinedwithclinicalassessmenthadsignificantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6e98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2e77.4), CA 125-II (62.8%; 95% CI, 52.2e72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8e84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8e96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4e76.4) for clinical assessment alone,35.7%(95%CI,20.7e54.2)forCA125-II,and78.6%(95%CI, 60.5e89.8) for modified ACOG guidelines.Early-stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9e99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8e82.2) for clinical assessment alone,75.9%(95%CI,63.5e85.0)forCA125-II,and75.9%(95%CI, 63.5e85.0) for modified ACOG guidelines. CONCLUSION: MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125-II, and modified ACOG guidelines with consistent performance across menopausal status.