Abstract: Case reports have indicated an increased risk of acute pancreatitis during use of selective serotonin reuptake inhibitors (SSRIs), an association not found in a few epidemiological studies. We studied the use of SSRI in relation to risk of acute pancreatitis in a population-based case-control study of people aged 40 to 84 years between 2006 and 2008 in Sweden. The Patient Register was used to identify 6161 cases of first-episode acute pancreatitis. The Register of the Total Population was used to randomly select 61,637 control subjects from the general population using frequency-based density sampling, matched for age, sex, and calendar year. Use of SSRI was defined as “current,” “recent,” “past,” or “former” if the drug had been dispensed 1 to 114 days, 115 to 180 days, 181 to 365 days, or 1 to 3.5 years before a given index date, respectively. Logistic regression with adjustment for potential confounding factors was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). The OR for acute pancreatitis, adjusted for matching variables, was increased among present users of SSRI (OR, 1.5; 95% CI, 1.4–1.7). After adjusting for diseases or medications related to alcohol overconsumption, tobacco smoking, diabetes, ischemic heart disease, obesity, and severe pain together with educational level and marital status, the corresponding OR was 1.1 (95% CI, 1.0–1.3). After adjusting for the number of distinct medications, a proxy for comorbidity, the corresponding OR was 1.0 (95% CI, 0.9–1.1). The OR for antidepressant use other than SSRI showed a similar pattern. In conclusion, no increased risk of acute pancreatitis remained among users of SSRI after adjusting for confounding factors.