Objectives: To assess the effect of an intervention with an Eicosapentaenoic Acid-enriched oral nutritional supplement on chemotherapy tolerability in patients with advanced colorectal cancer. Methods: Thirteen patients diagnosed with stage IV colorectal cancer were included. Patients in the experimental group received 2 packs of supplement per day during 12 weeks plus dietary counseling. The control group only received dietary counseling. Patients were assessed for nutritional status, dietary intake, health related quality of life (HRQOL) and chemotherapy compliance. Results: Only patients in the supplemented group significantly increased their weight after the intervention. They also had better scores in important domains of HRQOL, compared to controls. Although not statistically significant, the supplemented group did not experience interruptions in their chemotherapy treatment compared to the control group, with more interruptions due to toxicity. Conclusions: The present study, although limited by sample size, points out towards a positive effect of the intervention on chemotherapy tolerability.