Among pancreatic resections, total pancreatectomy (TP) is generally considered to lead to significant impairments in patients’ quality of life (QoL). Aim of this work was to evaluate QoL and long-term complications in patients undergoing TP at a tertiary referral center. Forty-eight patients undergoing TP between 1994 and 2006 were identified; the 32 survivors (median follow-up 30.5 months) were interviewed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), and with an Institutional questionnaire on pancreatic exocrine-endocrine function. Mortality after surgical resection was zero, and there were no deaths related to the long-term complications. Overall QoL after TP was acceptable (median:5, scale from 1 to 7), despite a slightly decrease compared to the preoperative period (median:6). A significant impairment in QoL was found only in patients with malignancies (P<0.05). Twenty-nine patients (91%) complained of hypoglycemia, 72% of them at least once a week. Steatorrhea and abdominal pain were found in 66% and 44% of patients. Major impairments of leisure and work activities were reported in 56% and 31% of cases. In experienced centers TP is a viable and safe procedure. However TP substantially affects health status, and the risk for long-term complications should be well evaluated; therefore careful patient-selection and long-term follow-up are of paramount importance in this setting.