Evidence demonstrates that providing nutritional support to intensive care unit (ICU) patients within 24 hours of ICU admission reduces mortality. However, early feeding is not universally practiced. Changing practice in complex multidisciplinary environments is difficult. Evidence supporting whether guidelines can improve ICU feeding practices and patient outcomes is contradictory. To determine whether evidence-based feeding guidelines, implemented using a multifaceted practice change strategy, improve feeding practices and reduce mortality in ICU patients. Cluster randomized trial in ICUs of 27 community and tertiary hospitals in Australia and New Zealand. Between November 2003 and May 2004, 1118 critically ill adult patients expected to remain in the ICU longer than 2 days were enrolled. All participants completed the study. Intensive care units were randomly assigned to guideline or control groups. Guideline ICUs developed an evidence-based guideline using Browman's Clinical Practice Guideline Development Cycle. A practice-change strategy composed of 18 specific interventions, leveraged by educational outreach visits, was implemented in guideline ICUs. Hospital discharge mortality. Secondary outcomes included ICU and hospital length of stay, organ dysfunction, and feeding process measures. Guideline and control ICUs enrolled 561 and 557 patients, respectively. Guideline ICUs fed patients earlier (0.75 vs 1.37 mean days to enteral nutrition start; difference, -0.62 [95% confidence interval {CI}, -0.82 to -0.36]; P < .001 and 1.04 vs 1.40 mean days to parenteral nutrition start; difference, -0.35 [95% CI, -0.61 to -0.01]; P = .04) and achieved caloric goals more often (6.10 vs 5.02 mean days per 10 fed patient-days; difference, 1.07 [95% CI, 0.12 to 2.22]; P = .03). Guideline and control ICUs did not differ with regard to hospital discharge mortality (28.9% vs 27.4%; difference, 1.4% [95% CI, -6.3% to 12.0%]; P = .75) or to hospital length of stay (24.2 vs 24.3 days; difference, -0.08 [95% CI, -3.8 to 4.4]; P = .97) or ICU length of stay (9.1 vs 9.9 days; difference, -0.86 [95% CI, -2.6 to 1.3]; P = .42). Using a multifaceted practice change strategy, ICUs successfully developed and introduced an evidence-based nutritional support guideline that promoted earlier feeding and greater nutritional adequacy. However, use of the guideline did not improve clinical outcomes. Trial Registration anzctr.org.au Identifier: ACTRN12608000407392.