Introduction Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Some studies have reported a decrease in CVD in patients with RA using hydroxychloroquine (HCQ). Most of these have had fewer participants and have analyzed only composite outcomes. We aimed to identify the association between the use of HCQ in patients with RA and the incidence of major adverse cardiac events (MACEs), cerebral infarction, and AMI. Methods This was a retrospective observational study using the TriNetX Diamond Network. Propensity score matching (PSM) was used to equilibrate the cohorts. The dependent variables in our study were MACE, cerebral infarction, and AMI. Results A total of 2,261,643 patients with RA were identified. Approximately 6% had been prescribed HCQ. Of those prescribed HCQ, 80% (112,743) were females, while of those not prescribed HCQ, 72.5% (1,536,937) were females. HCQ was associated with lower rates of MACE (HR 0.827, 95%CI 0.8,0.86), cerebral infarction (HR 0.824, 95% CI 0.78,0.87), and AMI (HR 0.9, 95% CI 0.85,0.96). These associations were not seen in patients taking biologics. HCQ was associated with lower MACE in all other subgroups. Conclusion In conclusion, HCQ was slightly beneficial in decreasing MACE and cerebral infarction in patients with RA. These associations were significantly lower in patients taking methotrexate or biologics. Although there was a significant decrease in the risk of AMI in all patients with RA, these results were not replicated in subgroup analyses, and there was an apparent increased risk of AMI with the use of HCQ in patients using biologics. Supplementary Information The online version contains supplementary material available at 10.1007/s10557-022-07387-z.

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