Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. Muscle loss was similar between arms (–1.1% 95% CI, –6.1% to –4.0%; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 1.16-1.99; P < .001) and energy (OR, 1.59 1.21-2.08; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 μM 44-98 μM; P = .547) and trial day 10 (239 μM 33-444 μM; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 18.6-20.4) vs continuous feed (12.98 14.0-15.7; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov