Antimicrobial action of activated platelets against Staphylococcus aureus was known. Thrombocytopenia and higher patient mortality could be caused by S. aureus-induced platelet clearance. In a large national cohort of patients with S. aureus bacteremia, researchers investigated the effect of P2Y12 inhibition on clinical outcomes. Patients admitted to Veterans Affairs (VA) hospitals with blood cultures positive for S. aureus and treated with standard-of-care antibiotics were included in the retrospective cohort (2010–2018). Investigators compared clinical outcomes in patients treated with clopidogrel for at least 30 days before admission and at least 5 days after admission to patients who had not taken a P2Y12 inhibitor in the year before admission using propensity score-matched Cox proportional hazards regression models. Clopidogrel users had a reduced mortality rate than P2Y12 inhibitor nonusers (n=147 propensity score-matched pairs): inpatient mortality was 0.11 (95% CI, 0.01 to 0.86), and 30-day mortality was 0.43 (95% CI, 0.19 to 0.98). About 30-day readmission, 30-day S. aureus reinfection, microbiological clearance, and thrombocytopenia showed no differences. In a group of patients with S. aureus bacteremia, using clopidogrel at the time of infection reduced in-hospital mortality by 89% and 30-day mortality by 57%. The results emphasized the need for more research into P2Y12 inhibitors as an additional treatment for S. aureus bloodstream infections.