To examine whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with acute pancreatitis, a population-based case-control study was conducted in the counties of North Jutland (data 1991-2003), Aarhus (data 1996-2003), and Viborg (data 1998-2003), Denmark. Through hospital discharge registries, we identified all patients with an incident hospitalization of acute pancreatitis. From the Civil Registration System, we selected 10 sex- and age-matched population controls per case using risk set sampling. All prescriptions of SSRI and other antidepressant drugs within 90 days (present users) or 91 to 365 days (former users) before admission with acute pancreatitis, or index date among controls, were collected from prescription databases. First-time users were defined as those who redeemed their first SSRI prescription within 14 days before admission/index date. We estimated the relative risk of acute pancreatitis after exposure to SSRI or other antidepressants, adjusting for potential confounders. We included 3083 cases of acute pancreatitis and 30,830 controls. The adjusted odds ratio (OR) for acute pancreatitis in present users of SSRI was 1.2 (95% confidence interval [CI], 1.0-1.5); for former users, the adjusted OR was 1.2 (95% CI, 0.9-1.7). For current and former users of other antidepressant drugs, the corresponding adjusted ORs were 1.4 (95% CI, 1.1-1.7) and 1.4 (95% CI, 1.0-1.9), respectively. The adjusted OR of acute pancreatitis in first-time users of SSRI was 2.8 (95% CI, 1.1-7.0). We found use of SSRIs to be associated with increased risk for acute pancreatitis. However, the estimate did not differ between present or former users of SSRI and was not materially different from the estimate in users of other antidepressant drugs. Therefore, our data suggest that the increased risk is related to confounding by lifestyle factors or the underlying depression.