BACKGROUND: Because of its relatively low incidence, bladder cancer screening might have a better ratio of benefits to harms if it is restricted to a high‐risk population. Data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were used and simple decision analytic techniques were applied to compare different eligibility criteria for a screening trial. METHODS: For a variety of possible eligibility criteria, the percentage of the population aged 55 years to 74 years and classified as being at high risk for developing invasive or high‐grade carcinoma, and therefore likely to benefit from screening, was calculated. Regression models were used to calculate a risk score based on age, sex, smoking history, and family history of bladder cancer. The reduction in cases was calculated given hypothetical risk reductions associated with screening. The trade‐off between patients screened and tumors avoided was calculated as a net benefit. RESULTS: The 5‐year probability of being diagnosed with invasive bladder cancer was 0.24%. Using a risk score > 6 or > 8 as the eligibility criterion for a trial was generally superior to including all older adults. In a typical scenario, a risk score > 6 would result in approximately 25% of the population being screened to prevent 57 invasive or high‐grade bladder cancers per 100,000 population; screening the entire population would prevent only an additional 38 cases. CONCLUSIONS: Screening for bladder cancer can be optimized by restricting it to a subgroup of patients considered to be at elevated risk. Different eligibility criteria for a screening trial can be compared rationally using decision‐analytic techniques. Cancer 2013. © 2012 American Cancer Society. Different eligibility criteria for a screening trial of patients with bladder cancer were compared using decision‐analytic techniques. The optimal high‐risk subgroup for screening can be defined in terms of a risk score, based on age and sex as well as smoking and family histories.