Objective: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome. Design: Prospective, open label, multiple-center trial. Patients and Methods: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for ≥3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. Results: The patients enrolled in this survey were (mean ± SD) 62.8 ± 16.5 yrs old, with a body mass index of 25.1 ± 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 ± 13.6. Length of hospital stay was 29.1 ± 18.7 days (12.5 ± 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g·kg^-1·day^-1), was administered for 8.7 ± 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001). The fish oil dose·kg^-1·day ^-1 did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g·kg^-1·day^-1. Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g·kg ^-1·day^-1 were infused as compared with doses of <0.05 g·kg^-1·day^-1. After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g·kg ^-1·day^-1 and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. Conclusion: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.