Background: Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are widely prescribed for mood and anxiety disorders. However, it is not clear whether SNRIs are more strongly associated with cardiovascular and cerebrovascular events than SSRIs. Methods: This was a propensity score-matched, population-based, cohort study of Manitobans who started an SSRI or SNRI between April 1, 1998, and March 31, 2014. The primary outcomewas a composite of acute myocardial infarction (AMI), stroke, or cardiovascular-related hospitalization within 1 year of drug initiation. Each component of the primary outcome and death were analyzed separately in secondary analyses. Results: A total of 225,504 and 54,635 patients initiated treatment on an SSRI and SNRI, respectively. After propensity score matching, a higher risk was observed for the primary outcome among SNRI users (weighted hazards ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21). Secondary analyses showed that the risk of nonfatal stroke was higher among SNRI users (weighted HR, 1.20; 95% CI, 1.08-1.33). The risk of death was higher among SNRI users without mood and/or anxiety disorders (weighted HR, 1.17; 95% CI; 1.03-1.32). No differences were observed in the risk of AMI or fatal stroke between SSRI and SNRI use. Conclusions: New SNRI use was associated with a higher risk of nonfatal stroke relative to SSRI use. Further investigation is warranted regarding the higher risk of death observed in our subgroup analysis among incident SNRI users without mood and/or anxiety disorders.