Background:The use of aspirin as prophylaxis against venous thromboembolism (VTE) following total joint arthroplasty (TJA) has increased in popularity; however, the potential cardioprotective effects of aspirin when administered as VTE prophylaxis remain unknown. The present study investigated the influence of VTE prophylaxis, including aspirin, on mortality following TJA.Methods:We retrospectively reviewed 31,133 patients who underwent primary TJA from 2000 to 2017. Patient demographics, body mass index, and comorbidities were obtained from an electronic chart query. Patients were allocated into 2 cohorts on the basis of the VTE prophylaxis administered: aspirin (25.9%, 8,061 patients) and non-aspirin (74.1%, 23,072 patients). Mortality was assessed with use of an institutional mortality database that is updated biannually. Univariate and multivariate regression analyses were performed.Results:The overall mortality rate was 0.2% and 0.6% at 30 days and 1 year after TJA, respectively. The use of aspirin was independently associated with lower risk of death at both 30 days (odds ratio [OR], 0.39; p = 0.020) and 1 year (OR, 0.51; p = 0.004). Patients in the non-aspirin cohort showed 3 times the risk of death at 30 days compared with the aspirin cohort (0.3% compared with 0.1%; p = 0.004), and twice the risk of death at 1 year (0.7% compared with 0.3%; p < 0.001). At 1 year, the primary cause of death in the non-aspirin group was cardiac-related (46 of 23,072, 0.20%). In the aspirin group, the rate of cardiac-related death was almost 5 times lower (3 of 8,061, 0.04%; p = 0.005). Risk factors for mortality at 1 year included higher age (p < 0.001), male sex (p = 0.020), history of congestive heart failure (p = 0.003), cerebrovascular disease (p < 0.001), malignancy (p < 0.001), and history of prior myocardial infarction (p < 0.001).Conclusions:The present study demonstrates that the use of aspirin as prophylaxis against VTE following TJA may reduce the risk of mortality. Given the numerous options available and permitted by the current guidelines, orthopaedic surgeons should be aware of the potential added benefits of aspirin when selecting a VTE-prophylactic agent.Level of Evidence:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.