OBJECTIVE: The objective of the study was to determine the cost-effectiveness of annual screening tests for endometrial cancer. STUDY DESIGN: Markov state transition model of the natural history of endometrial cancer used as the design for the study. Incidence was modeled for the general population and high risk groups (obese, body mass index [BMI] of >or= 30 kg/m(2); tamoxifen users). Strategies evaluated were no screening, annual endometrial biopsy, annual endovaginal ultrasound, and annual serum screening. Serum screening was based on a recently described biomarker panel (sensitivity of 0.98, specificity of 0.98). RESULTS: In the general population model, no screening was least expensive, whereas annual serum screening age at 50-75 years had incremental cost-effectiveness ratio (ICER) of $60,363 per year of life saved (YLS) compared with no screening. In a high-risk population (obesity, BMI of >or= 30 kg/m(2)), annual serum screening at age 45-80 years had ICER of $41,226 per YLS compared with no screening. Annual endometrial biopsy and annual transvaginal ultrasound were dominated. CONCLUSION: Annual serum screening for endometrial cancer has the potential to be cost effective when applied to high-risk populations.