Background: The use of immune checkpoint inhibitors (ICI) in MSI-H/MMRd CRC patients has profoundly changed the treatment landscape in the metastatic setting; the most recent NICHE-2 trial showed 100% response rate in MSI-H/MMRd locally advanced CRC patients treated with neoadjuvant ICI, further highlighting the importance of identifying these patients accurately to enhance patient care. Here we report the concordance of NGS-MSI and IHC-MMR from a very large cohort of CRC tumors and study the molecular characteristics and clinical outcomes of these patients. Methods: A total of 28,105 CRC tumors were analyzed by NGS (592 genes, NextSeq or WES, NovaSeq) and IHC. MMRd was defined as complete loss of ≥1 IHC stains (MLH1, MSH2, MSH6, or PMS2) and proficient (MMRp) as any positive staining for all four proteins. MSI status was determined from over 7,000 target microsatellite loci covered by NGS. Central pathology review (CPR) of MMR IHC was done on 73 cases with discordant MMR/MSI results. Real-world overall survival was obtained from insurance claims and calculated from either tissue collection or treatment start to last contact; Kaplan-Meier estimates were calculated for molecularly defined patients. Results: For CRC tumors with NGS and IHC, 28031/28105 were concordant (99.74%), 0.09% were MMRd/MSS, and 0.2% were MMRp/MSI-H. After CPR, 23/24 (96%) of MMRd/MSS cases and 46/49 (94%) of MMRp/MSI-H were confirmed. Of the 46 post-CPR MMRp/MSI-H CRC samples, 52% had ≥1 pathogenic missense mutation in including MLH1/PMS2/MSH2/6 or MLH3, MSH3, PMS1 or POLE. Of the 23 post-CPR MMRd/MSS CRC samples, 38% had MLH1 loss, 91% PMS2 loss, no MSH2 loss and 9% MSH6 loss. When comparing clinical outcomes with concordant MSS/MMRp tumors, concordant MSI-H/MMRd patients had significantly longer OS (HR=1.131 [95% CI: 1.02-1.254], p<0.001) and post-ICI survival (HR= 2.695 [95% CI: 1.932-3.76], p<0.001). Compared to MSS/MMRd tumors (N=21), MSI-H/MMRp (N=29) trends to have longer OS (HR=2.163, [95% CI: 0.939-4.983], p=0.064) and insufficient ICI-treated patients were available for analysis. Conclusions: Here we report from >28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy.