Background: DNA mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) CRC is found in ~15% of early stage and ~5% of metastatic disease. Universal or reflex testing to identify dMMR/MSI-H has been proposed. The CRC incidence in young patients (pts) is also rising with unclear etiology. We present a large, single-institutional database of universal reflex dMMR/MSI-H testing in CRC comparing clinicopathologic and molecular profiles of younger (≤50) and older ( > 50) pts. Methods: For all CRC pts diagnosed at University of Florida between 2009-2017, reflex somatic testing for dMMR by IHC (MLH1, PMS2, MSH2, MSH6), MSI by PCR (Promega MSI kit) and NGS was performed with appropriate positive and negative controls. IHC protein loss was confirmed by second GI pathologist. Equivocal IHC results triggered MSI testing. Review of associated clinical EMR data was retrospectively performed and analysis conducted with student's t-test. Study was IRB approved. Results: 375 pts were analyzed by ≤50yo (n = 80; median age 44, range 17-50) or > 50yo (n = 295; median age 66, range 51-98). There was 100% concordance of MMR and MSI of all patient samples. dMMR/MSI-H incidence was 14% (11/80) in pts ≤50, compared to 22% (64/295) in pts > 50 (p < 0.001). For stage IV CRC, dMMR/MSI-H incidence was 4% vs. 13% (p = 0.003) between the age groups. Younger pts presented with more advanced disease (36% Stage III, 36% Stage IV) compared to older pts (32% Stage III, 26% Stage IV). Associated BRAF mutations were more common in pts > 50 (20% vs. 67%; p = 0.005). Conclusions: In our dataset, younger CRC pts are diagnosed with more advanced disease but with dMMR/MSI-H cancers at the expected rate. However, we identified more (likely sporadic) dMMR/MSI-H stage IV cancers in pts > 50yo than expected. Further studies to identify risk factors for younger patients and the ultimate clinical impact of universal reflex MSI testing is warranted to maximize IO therapy offering and survival.