Background: Microsatellite instability (MSI) and DNA mismatch repair defect (dMMR) are dependable predictive biomarkers of colorectal cancer (CRC) response to checkpoint inhibitors. We explored the correlation between mutations in genes encoding various DNA repair proteins and other genes to PD-L1 expression in CRC. Methods: In this study, 264 CRC tissue samples were collected in a community setting and were evaluated for molecular abnormalities. TP53, KRAS, BRAF, and PTEN mutations were detected with next generation sequencing, PTEN deletions with FISH, PD-L1 expression with IHC, MLH1 promoter methylation and MSI with PCR. Correlations were evaluated using standard statistical Chi Square and Kruskal-Wallis tests. Results: MSI in CRC correlated directly with age (P < 0.0001), MLH1 promoter methylation (P < 0.0001), and BRAF mutation (P < 0.0001), and inversely with PTEN (P < 0.0001), KRAS (P = 0.002), and TP53 (P = 0.005) mutations. PD-L1 expression directly correlated with MSI (P = 0.0047), MLH1 promoter methylation (P = 0.004), and BRAF mutation (P < 0.0001). There was no correlation between PD-L1 expression and TP53 or KRAS mutations. Conclusions: CRC has been shown to express immune checkpoint proteins differently than other cancers. While PD-L1 expression may not be a good predictor of response to checkpoint inhibition, MSI predicts benefit well. The demonstration of a direct correlation between MSI and BRAF and PTEN mutation suggests that therapy targeting these abnormalities may be effective when combined with checkpoint inhibitors. Prevalence and Correlations of Mutations, MSI, and PD-L1