OBJECTIVE: To estimate the risk of ovarian malignancy among asymptomatic women with abnormal transvaginal ultrasound scans or CA 125 and to provide guidance to physicians managing these women. METHODS: A cohort of women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with abnormal ovarian results at the initial (T0) and subsequent (T1+) screens were analyzed to estimate which findings were associated with high risk of ovarian cancer. Cancer risks more than 10% were designated as high and risks of 3% or less were designated as low. RESULTS: For the T0 screen, two high-risk categories were identified: CA 125 of 70 or more with negative transvaginal ultrasound scan (positive predictive value [PPV] 15.9%, CI 14.7-17.7%); and positive for both CA 125 and transvaginal ultrasound scan (PPV 25.0%, CI 23.3-27.3%). For T1+ screens, three high-risk categories were identified: negative transvaginal ultrasound scan with change in CA 125 of 45 or more (PPV 29.0%, CI 28.3-30.3%); increase in size of cyst 6 cm or more with negative CA 125 (PPV 13.3%, CI 10.5-18.0%); and positive for both tests (PPV 42.9%, CI 40.0-46.0%). High-risk criteria for T0 provide a sensitivity of 60%, specificity of 96.2%, PPV of 19.7%, and a negative predictive value (NPV) of 99.3%. T1+ criteria yielded a sensitivity of 85.3%, specificity of 95.6%, PPV of 29.6%, and NPV of 99.7%. CONCLUSIONS: High-risk categories for predicting risk of cancer in women with abnormal CA 125, transvaginal ultrasound scan, or both at initial and subsequent screens have been identified. The large number of women in this study, the 4-year complete follow-up, and small number of invasive cancers in the low-risk categories provide guidance for clinical decisions regarding need for surgery in these women. LEVEL OF EVIDENCE: II © 2012 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.