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Objective Chronic pancreatitis (CP) is a progressive fibro-inflammatory disease associated with increased comorbidity and mortality. This study aimed to characterise the natural history of CP by assessing comorbidity prevalence and mortality in a CP cohort.Methods A retrospective cohort study was performed at Nottingham University Hospitals NHS Trust, including patients diagnosed with CP between 1 January 2006 and 31 December 2014. Participants were followed up until 31 May 2023. Comorbidity prevalence was compared with national data from England in 2022 to calculate standardised prevalence ratios (SPRs). Similarly, standardised mortality ratios (SMRs) were also evaluated.Results Of the 1003 patients with CP, 678 who resided within the Greater Nottingham area were included in the study cohort. The overall median follow-up was 5.7 years (IQR 1.2–10.6). Compared with the general population, patients with CP had significantly elevated SPRs for heart failure (3.0; 95% CI 2.3 to 3.8), diabetes mellitus (2.4; 95% CI 2.1 to 2.7), ischaemic heart disease (2.4; 95% CI 2.0 to 2.8), atrial fibrillation (1.9; 95% CI 1.5 to 2.3) and cerebrovascular disease (1.4; 95% CI 1.0 to 1.8). The cumulative incidence at 20 years of diabetes mellitus, chronic liver disease and chronic kidney disease was 12%, 11% and 11%, respectively. During follow-up, 495 patients (73%) died, with median survival of 5.7 years (95% CI 4.8 to 6.4). The overall SMR of patients with CP was significantly increased (2.3; 95% CI 2.1 to 2.6; p<0.0001) compared with the general population. Leading causes of death were malignancy (27%), infections (22%) and cardiovascular disease (6.9%).Conclusion CP is associated with increased risk of multiple comorbidities and elevated mortality as compared with the general population. Enhanced surveillance and early intervention strategies may help prevent or delay the onset of these associated conditions.