BACKGROUND: How mild-to-moderate hypertriglyceridemia (2–10 mmol/L; 177– 886 mg/dL) potentially causes acute pancreatitis is unknown; however, cellular studies indicate that inflammation might be a driver of disease progression. We tested the hypotheses that (a) mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and that (b) the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis depends on low-grade inflammation. METHODS: From the Copenhagen General Population Study and the Copenhagen City Heart Study, 117 865 men and women 20–100+ years of age with measurements of nonfasting plasma triglycerides at baseline were followed prospectively for development of acute pancreatitis. RESULTS: After multivariable adjustment, a 1 mmol/L (89 mg/dL) higher nonfasting triglyceride concentration was associated with 17% (95% CI, 16%–18%, P = 3 × 10 ^-17 ) higher plasma C-reactive protein (CRP) and a 4.2% (4.0%–4.4%, P = 6 × 10 ^-17 ) higher blood leukocyte count. Higher concentrations of nonfasting triglycerides were associated almost linearly with higher risk of acute pancreatitis (P for trend = 5 × 10 ^-6 ), with hazard ratios of 1.5 (95% CI, 0.9–2.5), 2.0 (95% CI, 1.1–3.6), 2.2 (95% CI, 1.0–4.7), 4.2 (95% CI, 1.6–11.5), and 7.7 (95% CI, 3.0–19.8) in individuals with nonfasting triglycerides of 1.00–1.99 mmol/L (89–176 mg/dL; 46% of the population), 2.00–2.99 mmol/L (177–265 mg/dL; 17%), 3.00–3.99 mmol/L (266–353 mg/dL; 6%), 4.00–4.99 mmol/L (354–442 mg/dL; 2%), and ≥5mmol/L(443 mg/dL; 2%), respectively, vs individuals with <1 mmol/L (89 mg/dL; 27%). The association with risk of acute pancreatitis appeared more pronounced in individuals with CRP of ≥1.39 mg/L (P for trend = 0.001) and leukocytes of ≥7 × 10 ⁹ /L (P = 2 × 10 ^-4 ) than in those with CRP <1.39 mg/L (P = 0.03) and leukocytes <7 × 10 ⁹ /L (P = 0.04); however, there was no formal evidence of statistical interaction (P = 0.38 for CRP and P = 0.41 for leukocytes). CONCLUSIONS: Mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and higher risk of acute pancreatitis. The association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis is possibly partly mediated by low-grade inflammation.