Background: n-3 (omega-3) Fatty acids (FAs) may have beneficial effects in patients with cancer or in patients who undergo surgery or critical care. Objective: Our aim was to systematically review the effects of oral or enteral and parenteral n-3 FA supplementation on clinical outcomes and to describe the incorporation of n-3 FAs into phospholipids of plasma, blood cells, and mucosal tissue and the subsequent washout in these patients. Design: We investigated the supplementation of n-3 FAs in these patients by using a systematic literature review. Results: In cancer, the oral or enteral supplementation of n-3 FAs contributed to the maintenance of body weight and quality of life but not to survival. We did not find any studies on parenteral supplementation of n-3 FAs in cancer. In surgical oncology, we did not find any studies on enteral supplementation of n-3 FAs. However, postoperative parenteral supplementation in surgical oncology may reduce the length of a hospital stay. For general surgery, we did not find any studies on enteral supplementation of n-3 FAs, and evidence on parenteral supplementation was insufficient. In critical care, enteral supplementation of n-3 FAs had beneficial effects on clinical outcomes; evidence on parenteral supplementation in critical care was inconsistent. The incorporation of n-3 FAs in plasma and blood cells was slower with enteral supplementation (4-7 d) than with parenteral supplementation (1-3 d). The washout was 5-7 d. Conclusions: This review shows the beneficial effects of n-3 FA supplementation in cancer, surgical oncology, and critical care patients. Supplementation in these specific patient populations could be considered with the route of administration taken into account. © 2011 American Society for Nutrition.