The intervention protocol for an ovarian cancer screening trial should be efficient as well as effective, because it may become the standard of care if the trial demonstrates mortality reduction. To identify an efficient ovarian cancer screening protocol, the effectiveness and cost-effectiveness of selected single modality and multimodal screening strategies were estimated using a stochastic simulation model. Screening was simulated over a 30-year period in a hypothetical cohort of 1 million women aged 50 at the beginning of the period. The net present value of the cost per year of life saved was estimated for six protocols involving transvaginal sonography (TVS) and/or the tumor antigen CA 125. Internal and external validation was performed, and sensitivity analyses were conducted to assess the robustness of the ranking of the strategies. A multimodal strategy involving CA 125 with a threshold for positivity of either elevation above 35 U/ml or doubling since the previous screen, followed by TVS only if CA 125 is positive, was found to be efficient in the sense that no other strategies saved as many years of life at lower cost per year of life saved. Used annually, this strategy cost under $100,000 per year of life saved over a range of assumptions. The model's predictions are consistent with results reported in the literature regarding the performance of TVS and CA 125. The multimodal strategy used annually or every six months was efficient compared to either ultrasound or CA 125 used alone, over a range of assumptions. Simulation of screening may be useful in selecting a screening protocol to be tested in a randomized controlled trial.