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Purpose: There is a subset of patients who do not tolerate vagotomy and gastric resection for peptic ulcer surgery. The patterns of failure after peptic ulcer surgery have changed over the past 30 years as the indications for surgery have narrowed. The purpose of this study is to describe a unique syndrome of chronic gastrointestinal failure in female smokers that require surgery for medically refractory peptic ulcer disease (PUD).Methods: A retrospective review was performed in a consecutive group of women that required gastric resection and vagotomy for refractory PUD. Medical records were reviewed for common factors and symptoms shared by this select group of patients. Results: A total of five women (n=5) are described. All women underwent gastric resection with vagotomy for PUD. All required multiple re-operations for failing to take an oral diet and failing to tolerate jejunal tube feedings.. All patients were white and the mean age was 47 year old. The mean BMI was 15 kg/m2. Other factors shared by this group include a significant smoking history, chronic narcotic abuse, constipation, chronic intolerance to oral diet, and failure to tolerate tube feeds at infusion rates that maintain adequate body weight. Conclusion: This study describes a distinctive syndrome of idiopathic gastrointestinal failure in female smokers that require surgery for medically intractable PUD. The syndrome is characterized by chronic intolerance to oral intake, intolerance to high volume enteral feeds, narcotic use, need for multiple gastrointestinal operations, and significant malnutrition manifested by weight loss and low BMI. Early identification of this syndrome may allow patients to avoid unnecessary interventions and allow clinicians to tailor nutritional support to individual patients.