OBJECTIVE To compare the efficacy of combination therapy, with erythromycin and metoclopramide, to erythromycin alone in the treatment of feed intolerance in critically ill patients. DESIGN Randomized, controlled, double-blind trial. SETTING Mixed medical and surgical intensive care unit. PATIENTS Seventy-five mechanically ventilated, medical patients with feed intolerance (gastric residual volume ≥250 mL). INTERVENTIONS Patients received either combination therapy (n = 37; 200 mg of intravenous erythromycin twice daily + 10 mg of intravenous metoclopramide four times daily) or erythromycin alone (n = 38; 200 mg of intravenous erythromycin twice daily) in a prospective, randomized fashion. Gastric feeding was re-commenced and 6-hourly gastric aspirates performed. Patients were studied for 7 days. Successful feeding was defined as a gastric residual volume <250 mL with the feeding rate ≥40 mL/hr, over 7 days. Secondary outcomes included daily caloric intake, vomiting, postpyloric feeding, length of stay, and mortality. MEASUREMENTS AND MAIN RESULTS Demographic data; use of inotropes, opioids, or benzodiazepines; and pretreatment gastric residual volume were similar between the two groups. The gastric residual volume was significantly lower after 24 hrs of treatment with combination therapy, compared with erythromycin alone (136 ± 23 mL vs. 293 ± 45 mL, p = .04). Over the 7 days, patients treated with combination therapy had greater feeding success, received more daily calories, and had a lower requirement for postpyloric feeding, compared with erythromycin alone. Tachyphylaxis occurred in both groups but was less with combination therapy. Sedation, higher pretreatment gastric residual volume, and hypoalbuminemia were significantly associated with a poor response. There was no difference in the length of hospital stay or mortality rate between the groups. Watery diarrhea was more common with combination therapy (20 of 37 vs. 10 of 38, p = .01) but was not associated with enteric infections, including Clostridium difficile. CONCLUSIONS In critically ill patients with feed intolerance, combination therapy with erythromycin and metoclopramide is more effective than erythromycin alone in improving the delivery of nasogastric nutrition and should be considered as the first-line treatment. ( Crit Care Med. 2007;35:2561-2567.) NQ Nguyen, M Chapman, RJ Fraser, LK Bryant, C Burgstad, RH Holloway.