Key PointsQuestionIs there any difference in treatment-related adverse events and outcomes between patients with early-onset (age <50 years) and older patients with metastatic colorectal cancer (mCRC)?FindingsIn this cohort study of 1223 patients with mCRC from 3 clinical trials, early-onset mCRC had significantly worse survival and displayed unique patterns of treatment-related adverse events. Analysis in a separate Moffitt Cancer Center cohort of 736 patients noted worse overall survival in early-onset mCRC and showed distinct genomic profiles in this population, which may partially explain the disparity.MeaningThese findings might have utility for an individualized approach to chemotherapy, counseling, and management of treatment-related adverse events in patients with early-onset mCRC.