Antiphospholipid (aPL) antibodies entailing anticardiolipin (aCL) and anti-beta2 glycoprotein I (anti-beta2GPI) antibodies may be involved in a number of vascular diseases including coronary artery diseases (CAD) or stroke. Here we assessed the presence of aPL antibodies in acute coronary syndrome (ACS). The frequency of anti-beta2GPI antibodies was significantly higher (14.4%) in ACS in comparison to control healthy subjects (2%). In addition, serum concentrations of anti-beta2GPI antibodies were also increased in ACS. Anti-beta2GPI antibodies of the IgA isotype might be the most relevant for the onset and outcome of ACS. Regarding subclasses of ACS, anti-beta2GPI IgA antibodies were elevated in unstable angina (UA) and myocardial infarction with ST elevation (STEMI), but not in myocardial infarction without ST elevation (NSTEMI). The involvement of anti-beta2GPI antibodies in ACS was more pronounced in men than women, and in younger rather than older patients. Finally, anti-beta2GPI antibodies in ACS were associated with previous stroke, but not with hypertension or previous myocardial infarction. Thus, anti-beta2GPI antibodies may be involved in the thrombotic events underlying ACS.