Background : In this study, the authors aimed to compare the effects that a medium‐ and long‐chain triglyceride (MCT/LCT) fat infusion and a fish oil–based (ω‐3) fat infusion for parenteral nutrition (PN) had on systemic inflammation, cytokine response, and hepatic steatosis in mixed intensive care unit (ICU) patients. Methods : This was a single‐center, placebo‐controlled, randomized clinical trial in a university hospital. Four patient groups, including systemic inflammatory response syndrome (SIRS) and sepsis patients, were assigned to receive PN employing the MCT/LCT fat infusion or the fish oil–based fat infusion over 7 days. Blood biochemistry and liver steatosis were evaluated. Results : Twenty sepsis and 20 SIRS patients were included in this study. There was no statistically significant difference in terms of biochemical values and Acute Physiology and Chronic Health Evaluation II scores between the different feeding groups. Sepsis groups who received MCT/LCT revealed higher grades of liver steatosis by ultrasound on days 7 and 10 ( P < .05). Tumor necrosis factor (TNF)–α and interleukin (IL)–6 values in sepsis group 1 (S1) were higher than in sepsis group (S2) on day 7, whereas IL‐1 values were higher on days 3, 7, and 10 in group S1 than in group S2. Conversely, IL‐10 values on days 3 and 7 were significantly higher in group S2. Conclusion : Fish oil–based fat emulsions might have anti‐inflammatory and hepatoprotective effects in hyperinflammatory disease such as sepsis.