A 64-year-old man with a family history significant for colon cancer was diagnosed with colorectal cancer, revealed to be moderately differentiated mucinous adenocarcinoma (stage IIIC) on biopsy. A tissue-based comprehensive genomic profiling of the cancer showed KRASG12D and ERBB2 amplification, microsatellite-stable, and TMB of 11mut/mB (FoundationOne)....The patient was started on pembrolizumab monotherapy, around 3.5 years after initial presentation. After five months on pembrolizumab, imaging showed significant improvement in pulmonary, hepatic, adrenal, and retroperitoneal metastases and the patient demonstrated partial response to treatment according to RECIST 1.1 criteria....This case demonstrates the existence of a subset of CRC patients who are MSS but TMB-H and may respond to immune checkpoint blockade.