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Our aim was to assess quality of life (QOL) and functionality in a large cohort of patients ≥5-years after pancreaticoduodenectomy (PD).Long-term QOL outcomes after PD for benign or malignant disease are largely undocumented.We administered the EORTC QLQ-C30 questionnaire to patients who underwent PD for neoplasms from 1998 to 2011 and compared their scores with an age- and sex-matched normal population. Clinical relevance (CR) of differences was scored as small (5–10), moderate (10–20), or large (>20) based on validated interpretation of clinically important differences.Of 305 PD survivors, 245 (80.3%) responded, of whom 157 (64.1%) underwent PD for nonmalignant lesions. Median follow-up was 9.1 years (range 5.1 –21.2 yrs). New-onset diabetes developed in 10.6%; 50.4% reported taking pancreatic enzymes; 54.6% reported needing antacids. Compared with the age- and sex-adjusted controls, PD survivors demonstrated higher global QOL (78.7 vs 69.7, CR small, P < 0.001), physical (86.7 vs 77.9, CR small, P < 0.001) and role-functioning scores (86.3 vs 74.1, CR medium, P < 0.001). Using linear regression and adjusting for socioeconomic variables, there were no differences in QOL or functional scores in the benign versus malignant subgroups. Older age at operation was associated with worse physical-functioning (−0.4/yr, P = 0.008). Taking pancrelipase (−6.8, P = 0.035) or antacids (−6.3, P = 0.044) were both associated with lower social-functioning scores.Patients who had a PD demonstrated better global QOL, physical- and role-functioning scores at 5-years when compared with age- and sex-matched controls. Approximately half of the patients required pancreatic enzyme replacement, while only 11% developed new-onset diabetes.