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Reactive oxygen species contribute to the cytotoxic effects of anticancer drugs; however, clinical relevance of systemic antioxidant capacity in metastatic colorectal cancer (CRC) remains unclear. This study examined the association of baseline blood antioxidant capacity with chemotherapy response and prognosis in 84 patients with stage IV CRC who underwent primary tumor resection followed by systemic chemotherapy between 2015 and 2020. Baseline antioxidant capacity was assessed preoperatively using biological antioxidant potential (BAP) assays. Chemotherapy response was evaluated using contrast-enhanced computed tomography at 4 months using Response Evaluation Criteria in Solid Tumors v1.1. Three-year disease-specific survival (DSS) was assessed. Associations with treatment response were analyzed using linear regression. Survival outcomes were evaluated using Kaplan–Meier and Cox proportional hazards models. Baseline BAP was significantly associated with poorer chemotherapy response; higher BAP levels predicted greater treatment resistance in multivariable analysis (P=0.013). Kaplan–Meier analysis demonstrated significantly worse 3-year DSS in the high-BAP group than in the low-BAP group (35.6% vs. 55.5%, log-rank P=0.019). In multivariate Cox regression analysis, high BAP independently predicted poor DSS (hazard ratio 2.174, 95% confidence interval 1.103–4.283, P=0.009). Elevated baseline systemic antioxidant capacity was associated with reduced chemotherapy effectiveness and poorer DSS in patients with stage IV CRC.