A small but significant percentage of patients with acute pancreatitis die within 2 weeks of hospitalization, usually with multiorgan system failure. To determine the effect of chronic medical comorbidities on early death, we conducted a retrospective analysis of all patients who were hospitalized in California with first-time pancreatitis between 1992 and 2002. Among 84,713 patients, 1514 (1.8%) died within 2 weeks. In a risk-adjusted multivariate model, the strongest predictors of early death were age 65 to 75 years (OR = 2.6, 95% CI: 2.2-3.1 versus <55 years), age over 75 years (OR = 5.2, 95% CI: 4.4-6.1), and the presence of either two chronic comorbid conditions (OR = 3.5, CI: 2.7-4.6) or three or more comorbidities (OR = 7.4, 95% CI: 5.7-9.5). Among the 14,280 patients younger than 55 years who had no chronic comorbid conditions, only 14 (0.1%) died in the first 14 days compared to 701 (5.9%) of 24,852 patients 64 years or older who had three or more comorbidities (RR = 29, 95% CI: 17-50). Comorbid conditions associated with early death included recent cancer, heart failure, renal disease, and liver disease. We conclude that advancing age and the number of chronic comorbid conditions are very strong predictors of early death among patients with acute pancreatitis.