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Introduction: Although mortality after pancreatoduodenectomy (PD) has decreased over the past decades, morbidity remains still high. We therefore aimed to identify risk factors that might preoperatively predict postoperative complication rates.Methods: From 1994 to 2009 544 consecutive patients underwent PD as pylorus preserving pancreatic head resection (83%) or the classical Whipple-procedure (17%). Indications for surgery were pancreatic (PaCa, 36%) or other periampullary cancers (23%), chronic pancreatitis (CP, 29%) and others (12%). During subgroup analysis patients with remaining ‘hard’ pancreatic gland (PaCa or CP; 66%) were compared with the other pathologies (‘soft’ pancreas). Evaluation was done by retrospective analysis of our prospective pancreatic database. Multiple demographic and disease-related parameters were analyzed for their influence on various complication types (multivariately by binary logistic regression). For this study pancreatic leak included all 3 ISGPS-definitions. 15% of the patients had resection of adjacent organs (OrgRes), 10% preoperatively elevated creatinine levels (CreaHigh).Results: Overall mortality was 3.2% (no risk factor identified). Overall complication rate was 56% and independent on the type of PD. Surgical complications occurred in 38%, infectious surgical complications in 19% and any pancreatic leak in 18%. Multivariate risk factors for any complication were ‘soft’ pancreas (no PaCa/CP; p<0.01, relative risk RR 1.8), OrgRes (p<0.001; RR3.2), CreaHigh (p<0.04; RR 1.8) and BMI >25 (vs < 25; p<0.04; RR 1.6). An elevated BMI > 25 and a ‘soft’ pancreas were independent risk factors for surgical complications (both p<0.01), infectious surgical complications (p<0.01/<0.03) and pancreatic leak (both p<0.01). Elevated BMI was the only risk factor for wound infections (p<0.03). Further factors like gender, antibiotic treatment, diabetes and preoperative stent did not relevantly influence morbidity.Conclusion: In our large series of patients undergoing PD an elevated body mass index and a potentially soft pancreatic remnant (defined by underlying disease/absence of stasis/pancreatitis) were clearly the most relevant factors predicting postoperative complications. These patient and disease related parameters should be considered in individual therapy planning and in perioperative outcome studies.