Background: Presentation of neoantigens, short peptides derived from tumor-specific somatic mutations, by HLA molecules triggers the activation of anti-tumor immune response. Recognition of neoantigens by autologous T cells promotes sensitivity to immune checkpoint inhibitors (ICI) in mismatch repair deficient (MMRd)/microsatellite instability high (MSI-H) tumors. Neoantigen-targeted reactivity has also been reported in microsatellite stable (MSS) tumors, and neoantigens are emerging targets for tumor vaccines and adoptive cell therapy. Here, we aimed to comprehensively assess the spectrum of immunogenic neoantigens in CRC to identify new subpopulations for these therapeutic strategies. Methods: 7,053 CRC tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (720-gene panel) and RNA (whole transcriptome) were analyzed. MSI status was determined by immunohistochemistry of MMR proteins and/or NGS. Immune epitope prediction was performed on translated peptide sequences harboring detected mutations using the NetMHCpan v4.0 method in the Immune Epitope Database, with HLA genotyping performed using arcasHLA. Immune/stromal cell abundance in the tumor microenvironment (TME) was estimated from RNA expression profiles using MCP-Counter. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature, TIS). Results: 6,600,005 unique peptide:allele interactions were tested, of which 368,468 (5.6%) were predicted neoantigens with patient-specific HLA alleles, including 16,184 (0.25%) with high affinity. MMRd/MSI-H tumors (6.9%) had higher neoantigen load at all affinity levels compared to MSS, with 10,243 (63.3%) and 5,621 (34.7%) of the predicted high affinity neoantigens exclusively associated with MSS and MMRd/MSI-H, respectively. 32 recurrent high affinity neoantigens were identified in > 10 samples, most frequently derived from APC mutations in MSS tumors (78% of recurrent neoantigens), and from RNF43 (25%), ASXL1 (20%), and KMT2D (15%) in MMRd/MSI-H. TIS scores positively correlated with the abundance of various immune cell populations in the TME, notably cytotoxic lymphocytes (r = 0.46). Among the recurrent high affinity neoantigens, those with the highest mean TIS scores (> 90^th percentile) resulted from mutation of MSH3 (K383fs, 5.1%) and KMT2D (multiple variants, 2.8%) in MMRd/MSI-H CRC, while those in MSS CRC derived from SOX9 (multiple variants, 0.2%) and APC (multiple variants, 0.7%) but were not associated with increased mean TIS scores (~55^th percentile). Conclusions: This is one of the largest studies to investigate the landscape of immunogenic neoantigens in CRC. We were able to identify candidate recurrent peptides with high HLA binding affinity and an association with a positive TIS signature supporting the role of neoantigens as potential cancer immunotherapy targets.