Aspirin (ASA) has been used for many years as an effective anti-platelet aggregation modality for a variety of cardio-protective and stroke prevention strategies. Since platelets play such an important role in the pathogenesis of endovascular infections such as endocarditis (IE), the potential utility of ASA in prophylaxis and/or therapy of such infections has been the subject of a number of investigations. In experimental models, the pretreatment of aortic catheterized animals with ASA reduced the extent of IE. Moreover, combinations of antibiotics + ASA appeared to have a synergistic impact in established experimental IE. In addition, ASA reduced the degree of renal embolization and vegetation size in these same models of established IE. Clinical trials have been less definitive on the salutary effects of ASA in endovascular infections. One large prospective trial of ASA to treat established IE showed no benefit in terms of reducing embolic events, with a trend towards increased bleeding episodes. However, cases of S. aureus IE were underrepresented in this trial. In contrast, another large recent retrospective analysis revealed a dramatic reduction in clinically-significant embolic events in patients on prior ASA use before the onset of their IE, especially in terms of CNS complications such as stroke syndromes. Finally, a recent investigation has suggested a reduction in chronic tunnel catheter-associated S. aureus bacteremias in hemodialysis patients on cardio-protective treatment with ASA. A number of in vitro studies have now explored the potential mechanism(s) of the anti-IE impacts of ASA, with the following conclusions: i) there are both anti-platelet and direct antimicrobial effects of ASA; ii) the antimicrobial effects are predominantly due to salicylic acid (SAL), the major biometabolite of ASA; iii) these ASA impacts are relatively specific for S. aureus and do not extend to other endovascular pathogens; and iv) the staphylococcal stress response pathway involving the alternative sigma factor, sigB, appears to be activated by ASA via SAL. Recent laboratory investigations have further evaluated genetic networks potentially involved in the ASA/SAL antimicrobial network in S. aureus and have implicated the agr, hla, mprF and sspA genes in this regard. Moreover, certain ASA structural congeners appear to have more potent anti-S. aureus effects against these aforementioned genes than the parental compound.