Background: Improvement of fat digestion and absorption was supposed to relieve feeding intolerance. This trial aimed to evaluate the effect of a fat-modified enteral formula on feeding tolerance in critically ill patients. Materials and Methods: This trial was conducted in 7 hospitals in China. In total, 144 intensive care unit (ICU) patients with estimated need of enteral nutrition (EN) for at least 5 days were randomly given fat-modified enteral formula containing medium-chain triglycerides (MCT), carnitine, and taurine (interventional feed group, n = 71) or standard enteral formula (control feed group, n = 73). EN intake, feeding intolerance (diarrhea, vomiting, gastric retention, and abdominal distension) and outcomes (mechanical ventilator-free days of 28 days, length of ICU stay, length of hospital stay, and in-hospital mortality) were collected. Results: Daily calories and protein intake were increased in the interventional feed group compared with the control feed group (P < .01). Total incidence of feeding intolerance was 42.3% in the interventional feed group and 65.7% in the control feed group (P < .001). Daily incidence of feeding intolerance was 11.3%, 18.3%, 14.1%, 25.4%, and 26.1% in the interventional feed group and 31.5%, 32.9%, 34.2%, 34.2%, and 30.4% in the control feed group from study days 1–5 (P = .0083). Incidence of feeding intolerance without abdominal distention was 32.9% in the interventional feed group and 49.3% in the control feed group (P = .047), while the incidence of abdominal distension was 26.8% in the interventional feed group and 43.8% in the control feed group (P = .03). No significant differences existed in outcomes between the 2 groups. Conclusions: The fat-modified enteral formula containing MCT, carnitine, and taurine may improve feeding tolerance in critically ill patients.