OBJECTIVE To characterize the current state of evidence and apply simulation modeling to support decision making about provision and coverage of a Lynch syndrome (LS) screening program among colorectal cancer (CRC) patients in our integrated healthcare delivery system. STUDY DESIGN Application of multiple methods for synthesizing evidence guided by needs of our clinical and administrative decision makers. METHODS Narrative and focused reviews, computerized simulation models of multiple screening options, queries of our electronic data warehouse, and extensive communication with decision makers. RESULTS Review of published evidence at the time of the study period revealed that screening unselected CRC patients for LS would likely cost less than $25,000 per life-year saved (compared with no screening) and that screening with immunohistochemistry is substantially more efficient than other options. Our simulation models suggest that not only does including BRAF mutation testing substantially improve efficiency but that adding methylation testing improves it further. We characterized a variety of other metrics that contributed not only to local decisions but to the broader evidence base on this topic. CONCLUSION The current state of evidence at the time of the study period suggests an LS screening program can be both effective in reducing mortality from CRC and cost-effective. However, direct evidence remains limited and multiple factors could threaten success of such a program. We have identified opportunities for optimizing the efficiency of available screening protocols. While there was enough evidence for our system to proceed with an LS screening program, we recognize the threats to program success and will prospectively collect outcome data supporting empirical examination of the program.