Background: UKCTOCS is the largest randomized controlled trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum CA125 interpreted with a risk algorithm; annual transvaginal ultrasound; or no screening (NS). There was a non-statistically significant 15% reduction in mortality over 11 years in MMS group. As most of the potential benefit of screening was seen after 7 years, follow-up is ongoing to determine if an observed stage shift translates into significant mortality reduction. The current study estimates the cost-effectiveness of an MMS screening program in the US. Methods: A modified Markov model was constructed using data from UKCTOCS to compare MMS to NS. Published estimates of the long term effect of MMS screening on ovarian cancer mortality were used to simulate mortality over 40 years from the start of screening. Base case costs included CA125, ultrasounds, clinical evaluations and false-positive surgeries, with an annual weighted cost of $35 in addition to an estimated risk algorithm cost of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2016 U.S. dollars per quality-adjusted year of life saved (QALY). Additional sensitivity analyses were performed. Results: MMS is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than NS. Screening women from age 50 to 75 with MMS reduced mortality by 24% with an ICER of $98,062/QALY. If screening begins at age 60, MMS reduces mortality by 12%, with ICER below the willingness to pay threshold of $100,000/QALY only if the algorithm costs < $50. In probabilistic sensitivity analyses, the probability that screening from age 50-75 at an algorithm cost of $100 was less than $100,000/QALY was 41%. Conclusions: Ovarian cancer screening is potentially cost-effective in the US depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.