INTRODUCTION: Pancreatic duct obstruction is the primary indication for endoscopic and/or surgical therapy in patients with chronic pancreatitis (CP). However, the clinical course of medically managed patients in relation to pancreatic duct obstruction is largely unknown. METHODS: This was a retrospective cohort study of medically managed patients with CP. We classified patients based on pancreatic duct obstruction from a stricture or stone using cross-sectional imaging (i.e., large vs small duct CP). We compared prevalence of diabetes and exocrine insufficiency (EPI) between subgroups at inclusion and investigated risk of new-onset diabetes, EPI, and all-cause mortality over a follow-up period of 5 years. Changes in pancreatic morphology were studied in patients who underwent follow-up imaging. RESULTS: A total of 198 patients (mean age 58 ± 12 years, 70% male, 60% alcoholic etiology, 38% large duct CP) were evaluated. At inclusion, patients with large vs small duct CP had a higher prevalence of both diabetes (43% vs 24%, P = 0.004) and EPI (47% vs 28%, P = 0.007). There was an increased risk of new-onset EPI in patients with large duct CP (hazard ratio 1.72; 95% confidence interval [1.05-2.80], P = 0.031) and higher rates of pancreatic atrophy ( P < 0.001). No differences between groups were observed for new-onset diabetes and all-cause mortality. Conversion from small to large duct CP or vice versa during follow-up was observed in 14% of patients. DISCUSSION: In a medically managed cohort of patients, large duct CP was associated with increased risk of EPI and pancreatic atrophy compared with small duct CP.