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In April 2016, the US Preventive Service Task Force (USPSTF) updated the aspirin guidelines for the primary prevention of cardiovascular disease (CVD) and colorectal cancer. This review assesses the importance of appropriate use of aspirin for the primary prevention of CVD and, specifically, how individuals with psychiatric disorders may benefit from such use. This study examined how current prescribing practices of aspirin in a state psychiatric hospital align with these new guidelines and how inappropriate prescribing may jeopardize patient safety. A retrospective chart review of 93 patients was performed to evaluate whether aspirin therapy would be recommended for primary prevention of CVD based on the new USPSTF guidelines. A secondary analysis of these data was performed using the 2009 USPSTF recommendations to strengthen the assumption that practitioners were no longer using the old guidelines. Drug interactions between aspirin and concurrently prescribed pharmacotherapy were classified based on of severity, and the past events of bleeding were quantified. Based on the 2016 guidelines, 25 of the 93 patients included in this study were identified as potential candidates who would benefit from aspirin use for the primary prevention of CVD; of whom 22 (88%) were not prescribed aspirin. The remaining 68 patients did not meet the criteria for aspirin use for primary prevention, although 11 (16.2%) of these patients were taking low-dose aspirin. Based on the 2009 guidelines, 49 of the 93 patients included in our study would have been identified as potential candidates who would benefit from the use of aspirin for the primary prevention of CVD; 41 (83.7%) of whom were not prescribed aspirin. The remaining 44 patients did not meet the previous criteria for aspirin use for primary prevention, although six (13.6%) of these individuals were taking low-dose aspirin daily. The results above indicate a difference between prescribing practices of aspirin use for the primary prevention of CVD. We identified a similar rate of underuse; however, there was a slight increase in the appropriate prescribing according to the 2016 guidelines compared with the 2009 guidelines (88 vs. 83.7%, respectively). Also, there was a higher incidence of unnecessary prescribing (overutilization) of aspirin for the primary prevention of CVD in 2016 compared with 2009 despite the more restrictive criteria (and smaller candidate pool) published in these newer guidelines. There were 47 drug interactions identified when patients’ aspirin and concurrent medication regimens were reviewed for our entire sample population. These interactions could potentially lead to an adverse drug reaction in the future. Our safety analysis revealed that none of the patients who were prescribed aspirin had any bleeding events while on therapy within the period of this study. Inappropriate omission of aspirin (underutilization) was more prevalent in our psychiatric institution than overutilization; however, the overall percentage of both underuse and overuse were greater when patients were evaluated according to the 2016 guidelines and then compared with the 2009 statistics. Overutilization did not pose a serious risk for those on aspirin therapy in this sample, as there were no major episodes of bleeding. However, future harm from aspirin still exists based on the significant number of major and moderate potential drug interactions with aspirin and the increased risk of decreased adherence to critical psychiatric medications due to increased pill burden and regimen complexity. Our findings demonstrate that there is an opportunity to educate prescribers on the updated 2016 USPSTF guidelines to improve preventive care and patient safety, which include harm reduction by initiating aspirin in those who are at a risk of cardiovascular events, continuing aspirin in those who are currently receiving aspirin appropriately, and discontinuing aspirin in those who are not considered to be at a high risk of CVD and who may also be at a risk of experiencing an increased risk of bleeding.