Background/Aims: The autosomal dominant disorder, the Lynch Syndrome (LS), with an estimated prevalence of .5-1% dramatically increases cancer susceptibility. It is associated with a 40-60% lifetime risk of colorectal and/or endometrial cancers of younger onset and accelerated progression. LS is a mismatch repair gene mutation of: MLH2 (39% of cases), MLH1 (32%), MSH6 (14%), and/or PMS2 (14%). LS tumors typically exhibit microsatellite instability(MSI), are never associated with BRAF mutation, and Immunohistochemistry (IHC) staining can indicate a particular mismatch repair gene mutation. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend LS testing to identify LS families. The goal is to reduce cancer-related morbidity, mortality, and—potentially—healthcare costs. However, insufficient evidence to recommend a specific strategy was found. We evaluate the health impact and cost-effectiveness of four strategies suggested by EGAPP. Methods: A microsimulation model of LS inheritance and cancer occurrence across three generations reflective of the 2010 US population compared four strategies: 1)sequential germline testing (MSH2, MLH1, MSH6, PMS2) of newly diagnosed cancers with targeted germline testing of relatives, 2) MSI testing of newly diagnosed cancers with sequential germline testing and subsequent targeted germline testing of relatives, 3) IHC staining of newly diagnosed cancers to guide germline testing with subsequent targeted germline testing of relatives, and 4) IHC staining with subsequent BRAF testing and targeted germline testing of newly diagnosed cancers and subsequent germline testing of relatives. Results: For all strategies among LS families, the proband typically came from older two generations with health benefits being mostly accrued by the youngest generation. Incremental to the base case representing current screening rates and technologies, strategy 1 saved 139,640 quality-adjusted life years (QALYs) for an estimated cost-effectiveness ratio of $101,306/QALY saved. Strategy 2 saved 96,238 QALYs for an estimated cost-effectiveness ratio of $27,545/QALY saved. Strategy 3 saved 51,422 QALYs for estimated cost effectiveness of $45,625/QALY saved, and strategy 4 saved 55,422 QALYs and estimated cost-effectiveness of $85,245/QALY saved. Conclusion: Although none of the strategies were cost-saving, initial MSI testing followed by subsequent relative screening could yield meaningful health benefits at acceptable costs.