Intravenous erythromycin is a potent gastric prokinetic with demonstrated efficacy in the acute therapy of gastroparesis; long-term oral therapy has been limited by tolerance and modest efficacy. Our aim was to review our experience with prolonged administration of intravenous erythromycin in an ambulatory setting as therapy for severe gastroparesis, refractory to usual dietary and oral prokinetic regimens. We conducted a retrospective analysis of patients with gastroparesis treated with intravenous erythromycin for at least 1 month. Information on demographics; origin of gastroparesis; dosage, duration, and route of administration; clinical outcome in the short- and longer-term; and complications were determined. Eleven patients received a total of 14 courses of intravenous erythromycin for a median of 6.5 months (range, 1 to 19 months) at a median dosage of 300 mg/day (range, 150 to 1,000 mg/day). One patient received no benefit, two had complete responses, and all others reported some benefit. Two had dramatic relapse on cessation of therapy and subsequently improved on its resumption. Parenteral nutrition could be discontinued in one of four patients. There were four episodes of line sepsis; two required catheter removal. A nonocclusive thrombus developed at the site of a central line in one patient. Secondary infections or antibiotic resistance were not encountered. Prolonged administration of intravenous erythromycin in an ambulatory setting is feasible, well tolerated, and effective in patients with severe gastroparesis.