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Antidepressants are commonly prescribed medications used in primary care. The cardiovascular safety profile of antidepressant medications, in terms of subclinical atherosclerosis, is underexamined.A total of 6814 participants in the Multi-Ethnic Study of Atherosclerosis were examined. At baseline, the mean age was 62 years with 4 race/ethnic groups represented: European Americans (38%), Hispanic Americans (23%), African Americans (28%), and Chinese Americans (11%). Antidepressants were subgrouped as serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and “other” (bupropion, nefazodone, trazodone, mirtazapine). After adjusting for potential confounders, we estimated the association between antidepressant use and the following measures of subclinical atherosclerosis: coronary artery calcium (CAC), the ankle-brachial index, and carotid intima-media thickness, both cross-sectionally and prospectively.A total of 324 participants were exposed to SSRIs, 88 to TCAs, 41 to SNRIs, and 123 to other antidepressants. For CAC incidence, the fully adjusted longitudinal analyses revealed no consistent associations with SSRIs (relative risk [RR], 0.99; 95% confidence interval [CI], 0.71–1.37), SNRIs (RR, 0.49; 95% CI, 0.13–1.86), TCAs (RR, 0.94; 95% CI, 0.50–1.77), other antidepressant (RR, 0.87; 95% CI, 0.73–1.03) exposure, and subclinical disease. Similar null results were obtained in the cross-sectional and longitudinal exposure to antidepressants with changes in baseline CAC greater than 0, ankle-brachial index, and carotid intima-media thickness.The results of the current study do not support an association between antidepressants and subclinical atherosclerosis.