Abstract Background: The incident of early onset of colorectal cancer (EOCRC) is increasing in adults including in African Americans (AA). Aim: To investigate differences between EOCRC compared to late onset colorectal cancer (LOCRC) in AA patients. Methods: We reviewed demography, pathology and colonoscopy records of patients seen at Howard University Hospital from 1959 to 2023. This retrospective cohort consists of 175 EOCRC cases (<45 years) and 2025 LOCRC cases (>45 years). The age-adjusted rates for EOCRC and LOCRC were calculated for the age categories <45 and above 45. Results: The cohort comprised predominantly AA individuals (>85%). Gender distribution showed slightly more females (1074, 53%) than males, with no significant difference observed between EOCRC and LOCRC groups (p=0.94). Initial symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). Notably, EOCRC exhibited a higher incidence of abdominal pain (23.3% vs. 17.2%, p=0.05) and changes in bowel habits (24.4% vs. 14%, p=0.05) compared to LOCRC. However, other symptoms such as melena, hematochezia, weight loss, and anemia were less prevalent in EOCRC than in LOCRC. Additionally, comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent in EOCRC compared to LOCRC. Family history of colon cancer in first-degree relatives was notably higher in EOCRC (15.5%) compared to LOCRC (3.2%, p=0.01). Pathology reports indicated a higher occurrence of neuroendocrine tumors in EOCRC (2.8%) than in LOCRC (1.4%). Complications such as gastrointestinal bleeding and abdominal CT abnormalities were more frequent in EOCRC. Location-wise, EOCRC was primarily observed in the left sigmoid and rectosigmoid regions (p=0.01). Metastasis to other organs was more prevalent in EOCRC than in LOCRC (p=0.04) suggesting more aggressive and advanced lesions. Surgical interventions were slightly more common in EOCRC (80.4%) than in LOCRC (79.1%). Type of polyps and stage distribution showed some variations between the two groups. Interestingly, the incidence of colorectal cancer showed fluctuations over the years, peaking between 1980 and 1989 before declining in recent years, probably as a result of colonoscopy popularization. Conclusion: CRC incidence is increasing among young AA who display highly advanced and more metastatic tumors in comparison with LOCRC. While current screening programs seems to have decreased CRC prevalence in individuals older than 45, special attention needs to be addressed to young AA adults as well, to counter the observed trend, as they have the highest incidence of CRC among young population groups by race/ethnicity. Detailed analysis of the molecular landscape of EOCRC AA tumors is needed to understand the differential pathways and mechanisms defining these early onset cancers. Citation Format: Suryanarayana Reddy Challa, Mrinalini Deverapalli, Nasrin Farjana, Lakshmi Gayathri Chirumamilla, Reza Oskrouchi, Swetha Mynedi, Mudasir Rashid, Karthikeyan Senthilvelan, Babak Shokrani, Rabia Zafar, Angesom Kibreab, Farshad Aduli, Adeyinka Laiyemo, Zaki Sharif, Hassan Brim, Hassan Ashktorab. A comprehensive comparative analysis of African Americans’ early onset and late onset colorectal cancer: A 60 year study in underserved population serving hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1011.