OBJECTIVES: Serotonin is critical for maintaining platelet haemostatic function such as aggregation.  SSRI-induced upper gastrointestinal hemorrhage (UGIH) may occur through SSRI-induced inhibition of serotonin reuptake by platelets, leading to depletion of serotonin after several weeks of antidepressant (i.e. SSRI) treatment. The risk of SSRI-induced-UGIH has not been documented in a U.S. managed care population.  The purpose of this study was to compare the incremental likelihood of UGIH events with use of SSRIs and in combination with NSAIDs in a managed care population. METHODS: A retrospective study was designed using data from a large managed care claims database. Subjects were identified anytime between October 1, 2005 to September 30, 2006 (index-period) and classified into SSRI-users, NSAID-users or SSRI-NSAID concomitant users.  Each subject was matched to a control (non-SSRI/NSAID-user) based on their index date.  All subjects were treatment naïve 12 months prior to their pre-index period and followed for 12 months post index date to determine the risk of any UGIH event based on ICD-9-CM code.  RESULTS:  A total of 87,054, 275,476, 27,696, and 386,248 subjects were identified as SSRI-users, NSAID-users, concomitant-users and controls at index-period.  The control group was significantly (p<0.001) younger than the drug cohorts (31vs. 42years), lower (p<0.001) proportions of females (47% vs. 57%), and lower (p<0.001) burden of comorbid illness as measured by Charlson Comorbidity Index (0.15 vs. 0.50).  Compared to the controls, concomitant-users had 1.0% (OR = 3.32; 95%CI = 2.90-3.79), SSRI-users had 0.8% (RR = 2.59; 95%CI = 2.36-2.86), and NSAID-users had 0.5% (RR = 1.83; 95%CI = 1.69-1.97) cases with a diagnoses of UGIH.  CONCLUSIONS:  Current SSRIs that are recommended as first line therapy for depression is associated with a risk of UGIH within first 12-months either alone or in combination with NSAIDs.  Future research needs to estimate the economic burden of such bleeding events to managed care.