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Linezolid is a monoamine oxidase inhibitor that may increase the risk of serotonin syndrome in patients receiving combination selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). The objective of this study was to compare the incidence of serotonin syndrome when linezolid was administered alone and in combination with SSRIs or SNRIs.This was a retrospective case-control study of adult inpatients admitted to the University of Iowa Hospitals and Clinics who received linezolid between January 2010 and December 2014. Patients who received linezolid with or within 14 days of an SSRI or SNRI were eligible for inclusion in the combination therapy group. Patients who received linezolid alone were matched by age and gender to patients in the combination therapy group, and 3 monotherapy patients were included for each combination therapy patient. Clinical features consistent with serotonin syndrome were assessed using the Sternbach and Hunter criteria.A total of 348 patients were included in this study, of which 87 received combination therapy and 261 received linezolid monotherapy. One patient given combination therapy (1.1%) and 1 patient given linezolid monotherapy (0.4%) were determined to have a diagnosis of serotonin syndrome (P = 0.438; relative risk, 3.00; 95% confidence interval, 0.19–47.45). In both cases, signs and symptoms of serotonin syndrome reversed upon discontinuation of linezolid therapy.There was no significant difference in the incidence of serotonin syndrome when linezolid was used alone or in combination with an SSRI or SNRI, and the overall incidence of serotonin syndrome was low.