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To investigate the association between venous thromboembolism (VTE) and antidepressant use in an Asian population.The authors conducted a nested case-control study of 1888 patients with VTE and 11,222 matched controls enrolled in the National Health Insurance Research Database in Taiwan from 2001 to 2009. The antidepressant exposure status and potential confounding factors were measured and included in the analyses. Conditional logistic regressions were applied to determine the effect of antidepressant use on VTE.We found a significant association of current antidepressant use with VTE in the total study sample (adjusted odds ratio [aOR], 1.59; 95% confidence interval (CI), 1.27–2.00). With regard to antidepressant classes and potency, we found that tricyclic antidepressants (aOR, 1.56; 95% CI, 1.11–2.18), serotonin 5-HT2A receptor blockers (aOR, 2.03; 95% CI, 1.27–3.24), and antidepressants with a low potency of serotonin reuptake inhibition (aOR, 1.57; 95% CI, 1.18–2.08) were associated with a significantly increased risk of VTE. When further stratifying by age, sex, and comorbid conditions, the VTE risk with antidepressant use was elevated among young and middle-aged adults, but not among the elderly. In addition, an elevated risk of VTE was observed in women and subjects without severe comorbid conditions, but not in men and subjects with severe comorbid conditions.There was a small increase in VTE risk with antidepressant use. The prescription of antidepressant drugs should be cautious, and especially, should be based on clinical evaluations of benefits and risks. The underlying mechanisms of the interaction between antidepressants and VTE warrant further investigation.