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ABSTRACT: BACKGROUND: Selective decontamination of the digestive tract (SDD) to eliminate gram-negative bacteria is still not widely accepted, although it reduces the incidence of nosocomial infections. In a previous retrospective study, a clear benefit to perioperative morbidity, and a reduction in nosocomial infections were found in patients who underwent an esophageal anastomosis. Thus, SDD was applied routinely for esophageal anastomoses. We report the outcome of a cohort of 81 patients who underwent this treatment. METHODS: From 2002, patients who underwent an esophageal anastomosis (esophagojejunostomy) were prospectively recorded. Perioperatively, patients received polymyxin, tobramycin, vancomycin and nystatin by mouth four times a day. Outcome was compared to a control group that was treated before 2002 (68 patients without SDD and 53 patients with SDD). Postoperative morbidity and mortality were assessed. RESULTS: Between 2002 and 2007, 81 patients who underwent an esophageal anastomosis received SDD. Compared to a retrospective control group, patients with SDD had significantly less pneumonia (OR 0.06 (0.01-0.46), p<0.001) and lower morbidity (OR 0.16 (0.05-0.49), p<0.001). Furthermore, fewer anastomotic insufficiencies and complications were found. Similar results were found in the analysis of the patients treated before 2002. CONCLUSIONS: SDD significantly reduces perioperative morbidity and mortality in patients who undergo a distal esophageal anastomosis compared to a historical control group. In patients with an anastomotic leakage, there was a strong tendency of SDD to reduce postoperative mortality.