OBJECTIVES: Serotonin syndrome (SS) is an adverse drug reaction that may occur in patients receiving monotherapy or combinations of serotonergic agents (SAs). This study examined healthcare utilization and costs of SS in two different populations. METHODS: Adult (age ≥18 years) patients prescribed SAs were identified using the Veterans Health Administration (VHA) dataset (01OCT2008-30SEPT2012) and the IMS PharMetrics Plus dataset (01JAN2010-31DEC2013). Patients with continuous health plan enrollment 12 months pre-index date, defined as the first SA prescription claim date, were included and observed until death, disenrollment or the end of the study period. Patients were assigned to cohorts based on drug exposure: single monoamine oxidase inhibitor (MAOI) drug, MAOI drugs in combination with other SAs, single non-MAOI SA, and multiple non-MAOI SAs (2, 3, 4, and ≥5 SAs). Outcomes of interest were annual incidences of SS event (ICD-9-CM: 333.99) and associated health care utilization and costs.  RESULTS: The incidence rate of SS was similar between veterans (VHA) and commercially insured patients (IMS) prescribed SAs and decreased over time (IMS: 0.17% in 2010 to 0.09% in 2013; VHA: 0.19% in 2009 to 0.07% in 2012). 0.88% and 4.35% of all SS events led to hospitalization in the IMS and VHA populations, respectively. Proportion of IMS patients with SS-related hospitalization increased as the number of non-MAOI SAs increased (0.24% for one drug vs. 6.93% for ≥5 drugs). Average healthcare cost per SS event was higher in the MAOI combination cohort (IMS: $2,474; VHA: $2,896) and the ≥5 non-MAOI SAs cohort (IMS: $1,167; VHA: $3,837) than the single non-MAOI SA cohort. CONCLUSIONS: The overall incidence of SS and proportion of serious SS leading to hospitalization are similar in the VHA and IMS populations. Use of MAOIs or multiple SAs concomitantly increases the risk of SS and leads to higher health care utilization and costs.