Background: While checkpoint blockade therapy has shown promise in mismatch repair-deficient CRC, these represent a small fraction of overall cases. Limited data exists regarding the immune microenvironment of mismatch repair-proficient CRC, hindering efforts to develop novel immunotherapy treatments for the majority of CRC patients. Methods: Quantification of immune subsets was evaluated by immunohistochemical (IHC) analyses in 23 primary MSI tumors, 45 primary MSS tumors and 34 untreated liver metastatectomy (LM) specimens for both center of tumor (CT) and invasive margin (IM) regions. Immunologic data, tumor microsatellite status, and consensus molecular subtype (CMS) were evaluated for possible correlations. Results: In CT, we found average CD3, CD4 and CD8 T cell infiltrates to be 6%, 3%, and 2% respectively for LM vs 9%, 4% and 5% for MSI vs 7%, 4% and 4% for MSS. In IM, we found average CD3, CD4, and CD8 T cell infiltrates to be 24%, 11% and 12% for LM vs 29%, 16% and 18% for MSI vs 25%, 14% and 12% for MSS. Higher T cell infiltrates were found in IM as compared to CT (p < 0.01) and there were fewer CD8 T cell infiltrates found in metastases as compared to primary tumors (p < 0.01). We observed higher average frequency of CD68 macrophages in LM in both CT (26%) and IM (55%) as compared to MSI (CT = 21%; IM = 32%; p < 0.01) and MSS (CT = 18%; IM = 32%; p < 0.01). Average CT PD-L1 expression on tumor cells was higher in MSI (27%) vs MSS (9%) and LM (3%). We did not observe significant differences between LM, MSI and MSS for CD45RO and granzyme-B expression. Stratified by CMS subtypes, CD8 T cell infiltration (p < 0.01) and PD-L1 expression on tumor cells (p < 0.01) were significantly higher in CMS1 (immune subtype). CMS3 (metabolic subtype) demonstrated higher expression of ICOS in CT (p < 0.05) and OX40 (CT p = 0.05; IM p < 0.01) than other subtypes. Conclusions: Our findings support evidence for efficacy of PD-1/PD-L1 blockade in CMS1 and suggest that CMS3 CRC subtype may benefit from unique immunotherapy combinations. These findings have important implications for future immunotherapy approaches in CRC and merit further investigation.