Objective: To assess whether the use of antidepressants with strong inhibition of serotonin reuptake is associated with a decreased incidence of ischemic stroke and myocardial infarction (MI). Methods: We conducted a cohort study using the United Kingdom Clinical Practice Research Datalink and considering new users of selective serotonin reuptake inhibitors (SSRIs) or third-generation antidepressants aged ≥18 years between 1995 and 2014. Using a nested case-control approach, each case of a first ischemic stroke or MI identified during follow-up was matched with up to 30 controls on age, sex, calendar time, and duration of follow-up. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) of each outcome associated with current use of strong compared with weak inhibitors of serotonin reuptake using conditional logistic regression. Results: The cohort included 938,388 incident users of SSRIs (n = 868,755) or third-generation antidepressants (n = 69,633). Mean age at cohort entry was 46 years (64% women). During follow-up, 15,860 cases of ischemic stroke and 8626 cases of MI were identified and matched to 473,712 and 258,022 controls, respectively. Compared with current use of weak inhibitors of serotonin reuptake, current use of strong inhibitors was associated with a decreased rate of ischemic stroke (RR, 0.88; 95% CI 0.80-0.97), but the effect size was smaller in some sensitivity analyses. The rate of MI was similar between strong versus weak inhibitors (RR, 1.00; 95% CI, 0.87-1.15). Conclusion: Our large population-based study suggests that antidepressants strongly inhibiting serotonin reuptake could modestly decrease the rate of ischemic stroke.