Abstract Objective The incidence of acute pancreatitis is rising worldwide and currently no curative treatment exists. Clarification of preventable risk factors is important for the reduction of morbidity and mortality from acute pancreatitis. In this study, we tested the hypothesis that the risk of acute pancreatitis associated with body mass index (BMI) is partly mediated through elevated triglycerides. Design We included 118 085 individuals from 2 prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, with BMI measured at baseline. Diagnosis of acute pancreatitis was assessed from the national Danish registries, as hospitalization or death due to acute pancreatitis. Results Higher BMI was associated with higher risk of acute pancreatitis with a multivariable-adjusted hazard ratio of 1.4 (95% CI, 1.1–1.8) for BMI of 25–29.9, 2.1 (1.6–2.9) for BMI of 30–34.9, and 2.8 (1.8–4.3) for BMI > 35, compared with individuals with BMI of 18.5–24.9. Triglycerides mediated 29% (95% CI, 12%–46%; P = 0.001) of the association between BMI and risk of acute pancreatitis in the age- and sex-adjusted model and 22% (6%–39%; P = 0.008) in the multivariable-adjusted model. Conclusion Higher BMI is associated with higher risk of acute pancreatitis in individuals from the general population, partly mediated through higher triglycerides. This indicates a potential for preventing acute pancreatitis by reducing BMI and triglycerides in individuals with high values.