Background: The rise of early-onset colorectal cancer (CRC) among non-Hispanic whites (NHW) compared to non-Hispanic blacks (NHB) points to race-specific etiology. Racial differences in clinical characteristics and survival differences for early-onset CRCs remain to be explored. Methods: Data from 4,012 CRC patients treated at the Siteman Cancer Center (2000-2015) was retrieved. We compared patient (insurance, comorbidities, family history of CRC) and clinical characteristics (site, stage, grade, histology), and treatment/surgical outcomes (surgery/radiation/chemotherapy, surgical approach, surgical margins, retrieved lymph nodes) according to race (NHB vs NHW) within 945 early-onset (<50 yr) and 1,580 average-onset CRC cases (≥65 yr), respectively. We then evaluated racial differences in 5-year survival. Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). Results: Compared to early-onset CRCs among NHW, NHB cases were more likely to present at the proximal (39% vs 23%) and distal colon (39% vs 33%) but less likely to be at the rectum (23% vs 44%) (P<0.001), while other clinical features were similar. Early-onset NHB CRC patients were less likely to have commercial insurance (47% vs 80%), more likely to enroll in Medicaid (32% vs 12%) or Medicare (9.4% vs 3.5%) (P<0.001), and present with a greater comorbidity score (23% vs 16%) (P=0.048). Five-year survival (crude rate 53% vs 61%) was slightly worse for early-onset NHB compared to NHW cases after adjusting for age, sex, year of diagnosis, and family history (HR=1.26; 95% CI 0.97-1.64), but the differences diminished after further adjustment for insurance, comorbidities, clinical features, treatment, and surgical outcomes (HR=1.12; 95% CI 0.83-1.50). Interestingly, except for advanced stage (IV: 34% vs 16%), minimal differences were observed for site/grade/histology when comparing early- vs average-onset NHB cases (P>0.05). In contrast, for NHW cases, in addition to advanced stages (IV: 33% vs 15%; P<0.001), early-onset CRCs are also more likely to be at the rectum (44% vs 38%) (P<0.001) and show high grade of differentiation (27% vs 22%; P<0.001) compared to NHW CRCs of average-onset. Conclusions: Our findings on differential tumor sites for early-onset NHB vs NHW CRCs as well as more advanced clinical characteristics of early-onset NHW cases compared to those of late-onset together call for deep molecular profiling of both early-onset NHB and NHW CRCs.