The objective of this study was to evaluate the relationship between increasing success with enteral nutrition (EN) and acquired infection in the Intensive Care Unit (ICU).We conducted a prospective, multicenter, observational study in 3 Medical/Surgical ICUs. We included patients mechanically ventilated in ICU more than 72h and who received enteral nutrition only. Charts were reviewed to determine success with EN delivery and clinical outcomes. Suspected infections were adjudicated by 2 or more clinicians to determine the presence or absence of infection (rated as either probable or possible infection).Of the 207 patients included in this analysis, the average age was 62.0 years; APACHE II score was 23.3; BMI: 28.5; and 73% were medical. Overall, patients received 48.9% (range 0–120%) of their energy and 45.1% (range 0–120%) of their protein requirements from EN. Overall, 25.1% developed an infection after 72h from admission, 21.7% developed an infection after 96h from admission, and the 28-day mortality was 29.0%. In a regression model, greater amounts of energy and protein were consistently associated with a reduction in infection. However, estimates only achieved levels near statistical significance for risk of at least 1 probable infection after >96h (Odds Ratio [0R]: 0.32, 95% Confidence Interval [CI]: 0.10–1.02, p=0.054 and OR: 0.40, 95% CI: 0.18–0.89, p=0.024 per 1000kcal/day energy and 30grams/day protein, respectively). In all cases, the OR was lower when considering infections that developed after 96h compared to infections that developed after 72h and when considering ‘Probable’ infections compared to all infections which included ‘Possible’ infections.Successful EN may be associated with a reduction in infectious complications, particularly after 96h of ICU admission.