PurposeTo investigate the association between the use of antidepressants and the risk of upper gastrointestinal tract bleeding (UGIB). MethodsA Case-control study was conducted in a Brazilian hospital complex. Cases were defined as patients with a diagnosis of UGIB and controls as patients admitted for reasons unrelated to gastrointestinal bleeding, gastric concerns, or complications associated with low-dose aspirin (LDA) or nonsteroidal anti-inflammatory drugs (NSAIDs) use. Sociodemographic and clinical data, comorbidities, drug therapy in use (long-term use and self-medication), and lifestyle habits were recorded through face-to-face interviews. Two groups were defined: use of antidepressants in general and use of antidepressants according to their affinity for serotonin transporters. The presence of synergism between the concomitant use of antidepressants and LDA or NSAIDs on the risk of UGIB was also explored. FindingsA total of 906 participants were recruited (200 in the case group and 706 in the control group). The use of antidepressants was not associated with the risk of UGIB (odds ratio [OR] = 1.503; 95% CI, 0.78–2.88) or the use of antidepressants with high affinity for serotonin receptors (OR = 1.983; 95% CI, 0.81–4.85). An increased risk of UGIB was observed in concomitant users of antidepressants and LDA (OR = 5.489; 95% CI, 1.60–18.81) or NSAIDs (OR = 18.286; 95% CI, 3.18–105.29). Despite the lack of significance, the use of antidepressants appears to be a positive modifier of UGIB risk in LDA and NSAID users. ImplicationsThese findings indicate an increased risk of UGIB in concomitant users of antidepressants and LDA or NSAIDs, suggesting the need to monitor antidepressant users, especially those most likely to develop UGIB. In addition, further studies with larger sample sizes are needed to confirm these findings.