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IMPORTANCE: Postoperative morbidity associated with pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) remains as high as 70%. However, to our knowledge, few studies have examined quality of life in this patient population. OBJECTIVE: To identify symptom burden and trajectories and factors associated with high symptom burden following PD for PA. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study of patients undergoing PD for PA diagnosed between 2009 and 2015 linked population-level administrative health care data to routinely prospectively collected Edmonton Symptom Assessment System (ESAS) scores from 2009 to 2015, with a data analysis undertaken in 2018. EXPOSURES: Baseline characteristics, including age, sex, income quintile, rurality, immigration status, and comorbidity burden, as well as treatment characteristics, including year of surgery and receipt of chemotherapy. MAIN OUTCOME AND MEASURES: The outcome of interest was moderate to severe symptoms (defined as ESAS ≥4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being. The monthly prevalence of moderate to severe symptoms was presented graphically for each symptom. Multivariable regression models identified factors associated with the reporting of moderate to severe symptoms. RESULTS: We analyzed 6058 individual symptom assessments among 615 patients with PA who underwent resection (285 women [46.3%]) with ESAS data. Tiredness (443 [72%]), impaired well-being (418 [68%]), and lack of appetite (400 [65%]) were most commonly reported as moderate to severe. The proportion of patients with moderate to severe symptoms was highest immediately after surgery (range, 14%-66% per symptom) and decreased over time, stabilizing around 3 months (range, 8%-42% per symptom). Female sex, higher comorbidity, and lower income were associated with a higher risk of reporting moderate to severe symptoms. Receipt of adjuvant chemotherapy was not associated with the risk of moderate to severe symptoms. CONCLUSIONS AND RELEVANCE: There is a high prevalence of symptoms following PD for PA, with improvement over the first 3 months following surgery. In what to our knowledge is the largest cohort reporting on symptom burden for this population, we have identified factors associated with symptom severity. These findings will aid in managing patients’ perioperative expectations and designing strategies to improve targeted symptom management.