Background Duodenal stump fistula (DSF) is the most severe surgical complication after gastrectomy. This study was designed to assess the incidence, to observe the consequences, and to identify the risk factors associated with DSF after gastrectomy. Methods All procedures involving total or sub-total gastrectomy for cancer, performed between January 1987 and June 2012 in a single institution, were prospectively entered into a computerized database. Risk factors analysis was performed between DSF patients, patients with complete uneventful postoperative course and patients with other major surgical complications. Results Over this 25 years period, 1287 gastrectomies were performed. DSF was present in 32 cases (2.5 %). Mean post-operative onset was 6.6 days. 19 patients were treated conservatively and 13 surgically. Mean DSF healing time was 31.2 and 45.2 days in the two groups, respectively. Mortality was registered in 3 cases (9.37 %), due to septic shock (2 cases) and bleeding (1 case). In monovariate analysis, heart disease (p \ 0.001), pre-operative lymphocytes number (p = 0.003) and absence of manual reinforcement over duodenal stump (p \ 0.001) were found to be DSF-specific risk factors, whereas liver cirrhosis (p = 0.002), pre-operative albumin levels (p \ 0.001) and blood losses (p = 0.002) were found to be non-DSF-specific risk factors. In multivariate analysis heart disease (OR 5.18; p \ 0.001), liver cirrhosis (OR 13.2; p \ 0.001), bio-humoral nutritional status impairment (OR 2.29; p = 0.05), blood losses [300 mL (OR 4.47; p = 0.001) and absence of manual reinforcement over duodenal stump (OR 30.47; p \ 0.001) were found to be independent risk factors for DSF development. Conclusions Duodenal stump fistula still remains a lifethreatening complication after gastric surgery. Co-morbidity factors, nutritional status impairment and surgical technical difficulties should be considered as important risk factors in developing this awful complication.