Few data are available with respect to quality of life (QoL) in long-term survivors after pancreaticoduodenectomy (PD). Aim of this study is to evaluate QoL and long-term outcomes in patients who underwent PD between 1990 and 2003 with a minimum follow-up of 48 months. Among 268 patients identified, 168 were still alive and were surveyed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), and with an Institutional questionnaire on long-term complications. Of the 168 surviving patients, 109 (65%) agreed to partecipate at a median of 7.5 years postoperatively. Pylorus-preserving pancreaticoduodenectomy (PPPD) was performed in 75% of cases; 56 patients (51.5%) had malignant neoplasms, 23 (21%) borderline tumors, and 30 (27.5%) benign neoplasms. Intraductal papillary mucinous neoplasms (IPMNs) was the most common indication for surgical resection (27.5%) followed by ductal adenocarcinoma (12%). Postoperative complications were recorded in 63 patients (58%). Overall, 75% of patients reported good scores in their perception of QoL. A significant decrease in QoL was found in patients with malignancy, with IPMNs, in survivors > 10 years, and in those with postoperative complications (P<0.05). Despite no significant differences in overall QoL perception, Whipple resection was more frequetly associated with alterations of functional and symptomatic domains than PPPD. 55% of patients complained of steatorrhea, 40% of dumping syndrome, 54% of weight loss. Dumping syndrome is not associated with Whipple procedure, while weight loss was more frequently observed after pancreo-gastrostomy than pancreo-jejunostomy. New endocrine insufficiency was found in 17% of cases. Recurrent abdominal pain was found in 41% of patients, who had also a significant impairment of QoL. PD is associated with acceptable QoL over time. However a careful long-term follow-up is necessary given the significant rate of exocrine insufficiency rate and impairments in digestive function. Patients who had complicated postoperative course, malignancies and who undewent PD with pancreogastric anastomosis are at higher risk of long-term complications and QoL impairments