Depression is a common disorder worldwide and is strongly associated with stroke. Use of antidepressants could potentially decrease the risk of stroke in patients with depression. However, the role of selective serotonin reuptake inhibitors (SSRIs), the most frequently prescribed antidepressant in this era, in the risk of stroke showed inconsistent results. We aimed to assess the association between the use of different types of antidepressants, SSRIs and tricyclic antidepressants (TCAs), and the risk of cerebrovascular events in patients with depression or anxiety. A nationwide population-based cohort study was retrospectively conducted in patients with depression or anxiety who started to take SSRIs and TCAs identified from the Taiwan National Health Insurance claims database (2001-2009). We examined the association between the 2 types of antidepressants and incidence of stroke using a proportional hazard model adjusted for stroke risk factors. Among the 24,662 SSRI and 14,736 TCA initiators, the crude incidence rate for stroke was 10.03 and 13.77 per 100 person-years, respectively. Selective serotonin reuptake inhibitor use was not associated with risk of stroke as compared with TCAs in the time-fixed analysis. After adjusting for baseline propensity scores in the time-varying analysis, SSRI use significantly reduced risk of stroke as compared with TCAs with the adjusted hazard ratio of 0.67 (95% confidence interval, 0.47-0.96). The effect persisted even after considering the antidepressant dosage (hazard ratio, 0.65 [0.42 to 0.99]). In summary, use of SSRIs was associated with a reduced risk for stroke, as compared with TCAs, in this specific disease population.