OBJECTIVES: Strategies for screening incident colorectal cancers(CRC) for possible Lynch syndrome(LS) are evolving rapidly. Our objective is to compare the diagnostic results and costs from two strategies for LS screening: Targeted Screening(TS) and Universal Screening(US) of tumors for mismatch repair(MMR) abnormalities. METHODS: For 18-months in 2010-2011, we employed TS - individuals under 60 years old and those meeting Bethesda criteria for LS. In 2012, we began US of all CRC. Immuno-histochemical(IHC) staining for the four MMR proteins was done in all cases. Microsatellite instability, BRAF mutation, MLH1 promoter methylation testing, and/or genetic testing of germ line DNA were done in selected cases. We modeled the diagnostic costs of several strategies for detecting LS, and the downstream costs of prevention CRC through colonoscopy screening, using a system dynamics model, built in the “Anylogic” program. RESULTS: In 2010-2011, 51 of 175 (29%) incident CRCs were screened by IHC using TS strategy; 15(29%) showed abnormal loss of >1 MMR protein. Germ line MMR gene mutations were found in 4 cases and were suspected but not demonstrated in 11 additional cases. In 2012-2013, 194 CRCs were screened by IHC using US; 13(6.7%) of CRCs had abnormal staining suspicious for LS. MMR mutations were found in only 2/9 cases abnormal for IHC. Cost to identify the LS probands was ~$8,339/LS case diagnosed for targeted screening (four mutation carriers/18 months) and ~$32,708/LS case diagnosed for universal screening (two mutation carriers/24 months). CONCLUSIONS: Real-world results were more complicated than anticipated. Results from US with IHC were often atypical, not diagnostic of LS. Economic analysis using our costs suggests that TS is less costly than US, but it will miss some cases of mildly penetrant LS. US identifies changes that are currently of unknown significance but that have potential to contribute to future research into the mechanisms of CRC tumorigenesis.