OBJECTIVES: The main objective was to assess cost-effectiveness of multimodal screening for ovarian cancer (Annual screening with CA125 marker, followed by transvaginal ultrasound for those at increased risk according to CA125 level) from the US societal perspective. The secondary objective was to facilitate an economic comparison between two different screening strategies (multimodal screening and ultrasound screening), which have been proven to be effective in improving early detection of ovarian cancer. METHODS: A lifetime incremental cost-effectiveness model was constructed to calculate the increase of costs, and QALYs gained by the multimodal screening. In this ‘backward induction’ model, the expected costs and outcomes for each 5-year time-interval are incorporated in subsequent 5-year time period calculations over the patient’s entire lifetime. The sensitivity and specificity of screening, and the stage distribution of detected ovarian cancer by the screening were obtained from the NCT00058032 clinical trial. The model used a 3% discount rate and reported results in 2009 US dollars. RESULTS: Over a lifetime, multimodal screening was estimated to cost an additional $820 with an expected gain of 0.0037 quality adjusted life years (QALY) or an incremental cost-effectiveness ratio (ICER) of $221,622/ QALY compared to no screening for age 65-69 postmenopausal females. Compared with annual transvaginal ultrasound (TVU) screening, multimodal screening improves cost-effectiveness by avoiding unnecessary TVU and surgery, which are risky to the patient and costly to the health care system. Cancer incidence rates and time required for screening exhibited substantial impact on the model from sensitivity analyses. CONCLUSIONS: Multimodal screening is not clearly cost-effective, compared to commonly accepted willingness-to-pay thresholds in oncology ($120,000-$150,000/QALY). If high risk women were selected for multimodal screening or if the screening was administered as part of another medical office visit in order to decrease the time required for screening test, the ICER could be lower than $120,000/QALY.