Abstract Purpose: Inflammation and angiogenesis are hallmarks of cancer development and progression. No studies have prospectively examined association of angiogenesis-related biomarkers with clinical outcomes in colon and rectal cancer. Patients and Methods: In pre-surgery serum samples from n=426 non-metastatic colorectal cancer (CRC) patients (stage I-III), we investigated associations of inflammatory (e.g., CRP, SAA, sICAM-1, sVCAM-1) and angiogenesis biomarkers (VEGF-A, VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed hazard ratios (HR) and 95% confidence intervals (CI). Analyses were adjusted for age, sex, body mass index, stage, tumor site, and study site, and also exploratory stratified by tumor site (colon vs. rectum). Results: N=65 patients (15%) were deceased and n=59 patients (15%) had a recurrence after a median follow-up of 31 months. Overall, doubling of CRP was associated with a ~24% increase in risk of death (OS: HRlog2: 1.24; 95% CI: 1.11-1.40), a 19% increase in risk of recurrence: HRlog2: 1.19; 95% CI: 1.08-1.32, and a non-statistically-significant 12% increase for DFS HRlog2: 1.12; 95% CI: 0.98-1.28. Similar associations were observed for SAA. Doubling of sICAM-1 was associated with a 4-fold increase in risk of death (OS: HRlog2: 4.05; 95% CI: 2.35-6.98). For the angiogenesis marker VEGF-D, significant heterogeneity was observed in analyses stratified by tumor site: doubling was associated with a 3-fold increase in risk of death for rectal cancer (OS: HR: 3.26; 95% CI: 1.58-6.70) and a 22% reduction in mortality for colon cancer (OS: HR: 0.78; 95% CI: 0.35-1.73; pheterogenity <0.001). Similar heterogeneity was observed in associations of VEGF-D with DFS and risk of recurrence, although not statistically significant (pheterogeneity<0.10). Conclusion: Our data suggest that some biomarkers of inflammation and angiogenesis are prognostic markers for stage I-III CRC patients, with potential differences by tumor site for angiogenesis markers. Citation Format: Jennifer Ose, Tengda Lin, Caroline Himbert, Christy A. Warby, Sheetal Hardikar, Juergen Boehm, Biljana Gigic, Petra Schrotz-King, Martin Schneider, Alexis B. Ulrich, David Shibata, Jane C. Figueiredo, Erin M. Siegel, Christopher I. Li, Adetunji T. Toriola, Cornelia M. Ulrich. Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3227.