Importance  Single-site studies have described an association between use of selective serotonin reuptake inhibitors (SSRIs) and adverse outcomes of surgery. Multicenter studies including a broad range of surgical procedures that explore rare outcomes, such as bleeding and mortality, and that account for indications for administration of SSRIs are needed.

Objective  To determine whether perioperative use of SSRIs is associated with adverse outcomes of surgery in a national sample of patients.

Design  Retrospective study of patients 18 years or older who underwent major surgery from January 1, 2006, through December 31, 2008, at 375 US hospitals. We used multivariable hierarchical models to estimate associations between SSRI use and our outcomes. Pharmacy data were used to determine whether a patient received an SSRI in the perioperative period.

Setting  Three hundred seventy-five US hospitals.

Participants  Five hundred thirty thousand four hundred sixteen patients 18 years or older.

Exposure  Perioperative use of SSRIs.

Main Outcomes and Measures  In-hospital mortality, length of stay, readmission at 30 days, bleeding events, transfusions, and incidence of ventricular arrhythmias.

Results  Patients receiving SSRIs were more likely to have obesity, chronic pulmonary disease, or hypothyroidism (P < .001 for each) and more likely to have depression (41.0% vs 6.2%, P < .001). After adjustment, patients receiving SSRIs had higher odds of in-hospital mortality (adjusted odds ratio, 1.20 [95% CI, 1.07-1.36]), bleeding (1.09 [1.04-1.15]), and readmission at 30 days (1.22 [1.18-1.26]). Similar results were observed in propensity-matched analyses, although the risk of inpatient mortality was attenuated among patients with depression. Sensitivity analyses suggest that, to invalidate our results, an unmeasured covariate would have to have higher prevalence and be more strongly associated with mortality than any covariate included in our models.

Conclusions and Relevance  Receiving SSRIs in the perioperative period is associated with a higher risk for adverse events. Determining whether patient factors or SSRIs themselves are responsible for elevated risks requires prospective study.