Patients with traumatic brain injury (TBI) have delayed gastric emptying and often require prokinetic drug therapy to improve enteral feeding tolerance. The authors hypothesized that metoclopramide was less efficacious for improving gastric feeding tolerance for trauma patients with TBI compared to trauma patients without TBI. A retrospective analysis was conducted of patients admitted to the trauma or neurosurgical intensive care unit who received gastric feeding from January 2006 to April 2008. Gastric feeding intolerance was defined by a gastric residual volume >200 mL or emesis with abdominal distension or discomfort. Patients with gastric feeding intolerance were given metoclopramide 10 mg intravenously every 6 hours, followed by a dose escalation to 20 mg, and then combination therapy with metoclopramide and erythromycin 250 mg intravenously every 6 hours if intolerance persisted. In total, 882 trauma patients (49% with TBI) were evaluated. TBI patients had a higher incidence of gastric feeding intolerance than those without TBI (18.6% vs 10.4%, P < or = .001). Efficacy rates for metoclopramide 10 mg, metoclopramide 20 mg, and metoclopramide-erythromycin were 55%, 62%, and 79%, respectively (P < or = .03). Metoclopramide failure occurred in 54% of patients with TBI compared to 35% of patients without TBI, respectively (P < or = .02), due to a greater prevalence of tachyphylaxis. Single-drug therapy with metoclopramide was less effective for TBI trauma patients compared to trauma patients without TBI. Combination therapy with erythromycin as first-line therapy for TBI trauma patients with gastric feeding intolerance is indicated if there are no contraindications or significant drug interactions.