Background: The etiology of the rising incidence of early-onset colorectal cancer (EOCRC), defined as in patients aged <50, remains unknown. EOCRC is diagnosed at advanced pathologic stages compared to average-onset colorectal cancer (AOCRC; age >60). We previously reported data for Stages I-III disease. In this analysis, we evaluated tumor genomic differences in stage IV EOCRC versus AOCRC. Methods: The cohort included 3212 patients diagnosed with stage IV colon or rectal cancer who had whole exome sequencing (WES) as part of clinical tumor-informed ctDNA testing (Signatera, bespoke mPCR NGS assay, Natera, Inc.). Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from tumor WES analysis. The prevalence of somatic variants, gene mutations and mutational signatures were compared between EOCRC and AOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between age groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 1070 patients with EOCRC (75.8% colon, 22.2% rectal, 2% unknown) and 2141 patients with AOCRC (80.2% colon, 18.3% rectal, 1.5% unknown) were included. No significant differences were found in the frequency of MSI and TMB status between age groups. In the TMB-Low/MSS group (EOCRC N=982; AOCRC N=1930), TP53 mutations were more common in EOCRC (62% vs. 54.5%, p=0.0036), but APC gene mutations were less common in EOCRC (59% vs. 65%, p=0.02). In the TMB-High/MSI-H group (EOCRC N=64; AOCRC N=182), BRAFand BEND4 mutations were less common in EOCRC (6.2% vs. 59.3%, p<0.001 and 6.2% vs 31.9%, p=0.036), but KRASgene mutations were more common in EOCRC (54.7% vs. 17%, p<0.001). BRAF V600E was the only significant single variant (0% vs 59.3% p<0.001). No significant differences were found in the TMB-High/MSS group (EOCRC N=24; AOCRC N=29). In the mutational signature analysis for the TMB-Low/MSS group, the clock-like signature was less frequent in EOCRC (76.9% vs. 85.4%, p< 0.001). In the TMB-High/MSI-H group, MMR deficiency signature was the most frequent signature, however no significant differences were found between EOCRC and AOCRC (81.25% vs. 85.71, p=0.42). In the TMB-High/MSS group, POLE exonuclease domain mutations signature was 2.2 times more frequent in EOCRC (62.5% vs. 27.6%, p<0.024). MMR deficiency signature was also less common in EOCRC vs. AOCRC (33.33% vs. 55.17%; p<0.10). Conclusions: Tumors in EOCRC harbored unique genomic alterations that varied between the TMB-Low/MSS, TMB-High/MSI-H, and TMB-High/MSS subpopulations. In TMB-Low/MSS tumors, similar gene mutations and genomic signatures were observed. However, the TMB-High/MSI-H and TMB-High/MSS subgroups harbored gene mutations and signatures that differed between age groups, suggesting that EOCRC may arise from uniquely different mutagenic processes in these subgroups.