Background: Enteral nutrition (EN) increases hyperglycemia due to high carbohydrate concentrations while providing insufficient protein. The study tested whether an EN formula with very high-protein- and low-carbohydrate-facilitated glucose control delivered higher protein concentrations within a hypocaloric protocol. Methods: This was a multicenter, randomized, open-label clinical trial with parallel design in overweight/obese mechanically ventilated critically ill patients prescribed 1.5 g protein/kg ideal body weight/day. Patients received either an experimental very high-protein (37%) and low-carbohydrate (29%) or control high-protein (25%) and conventional-carbohydrate (45%) EN formula. Results: A prespecified interim analysis was performed after enrollment of 105 patients (52 experimental, 53 control). Protein and energy delivery for controls and experimental groups on days 1–5 were 1.2 ± 0.4 and 1.1 ± 0.3 g/kg ideal body weight/day (P =.83), and 18.2 ± 6.0 and 12.5 ± 3.7 kcals/kg ideal body weight/day (P <.0001), respectively. The combined rate of glucose events outside the range of >110 and ≤150 mg/dL were not different (P =.54, primary endpoint); thereby the trial was terminated. The mean blood glucose for the control and the experimental groups were 138 (−SD 108, +SD 177) and 126 (−SD 99, +SD 160) mg/dL (P =.004), respectively. Mean rate of glucose events >150 mg/dL decreased (Δ = −13%, P =.015), whereas that of 80–110 mg/dL increased (Δ = 14%, P =.0007). Insulin administration decreased 10.9% (95% CI, −22% to 0.1%; P =.048) in the experimental group relative to the controls. Glycemic events ≤80 mg/dL and rescue dextrose use were not different (P =.23 and P =.53). Conclusions: A very high-protein and low-carbohydrate EN formula in a hypocaloric protocol reduces hyperglycemic events and insulin requirements while increasing glycemic events between 80–110 mg/dL.