Background: Patients younger than 50 years comprise roughly 10% of the total incidence of CRC, but the incidence in young patients is increasing. This study investigated genomic differences between younger and older CRC tumors to identify potential therapeutic targets for this patient population. Methods: DNA was extracted from formalin-fixed, paraffin-embedded sections from 4699 cases of colorectal cancer (4001 colon and 698 rectal). Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a mean specimen median sequencing depth of 688X for all coding exons and selected introns of up to 403 cancer-related genes. Younger patients with CRC were defined as < 40 years and older patients with CRC were defined as ≥ 55 years. P values were calculated using Fisher’s exact test; false discovery rate (FDR) and 95% confidence intervals (95%CI) were also calculated. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. In the colon cancer analysis, alterations in CTNNB1 (p < 0.001, FDR = 0.08) and MLH1 (p < 0.001, FDR = 0.03) were found to be more common in younger patients compared to older patients. Older patients were more likely to have alterations in APC (p < 0.01, FDR < 0.01) and FAM123B (p < 0.01, FDR = 0.03). In the combined colon and rectal analysis, CTNNB1 (p < 0.001, FDR = 0.07) and MLH1 (p < 0.001, FDR = 0.02) alterations were found to be more common in younger patients with CRC, and APC (p < 0.01, FDR < 0.01) was more commonly altered in older patients with CRC. When focusing on truncating mutations and deletions only, young rectal cancer patients were found to have a log ratio of 3.7 for lesions in FAM123B (p = 0.02, 95%CI: 0.08-0.96) compared to colon cancer. CTNNB1 was found to have a 1.5X rate of mutation in colon compared to rectal cancer, not reaching statistical significance. Conclusions: In this analysis, younger patients and older patients demonstrated similar overall rates of genomic alterations. However, younger patients with CRC exhibited an increased rate of alteration in CTNNB1 and MLH1. These data may provide support to explore the WNT signaling pathway as a potential therapeutic target for younger patients with CRC.