Most hospitals have reduced medical staff on weekends. Furthermore, a recent study on acute myocardial infarction suggested that weekend admissions were associated with higher mortality compared with weekday admissions. We sought to determine if compliance with guideline recommendations for acute coronary syndrome performance measures would be worse on weekends/holidays compared with weekdays. We utilized the American Heart Association's Get with the Guidelines (GWTG)--Coronary Artery Disease database. This study included 154,910 patients admitted to 515 various hospitals from January 14, 2000 to April 30, 2007 with acute coronary syndrome (ACS). Patients discharged on weekdays were older and were more likely to be women, have a history of atrial fibrillation, cerebral vascular accident/transient ischemic attack and chronic renal insufficiency, and present with unstable angina. Although patients discharged on the weekends/holidays were slightly less likely to receive angiotensin-converting enzyme inhibitors than those discharged on weekdays (68.3% vs 69.5%, p <0.0001), all other measures were similar, and a composite performance measure for 100% compliance was equal in both groups (81.5% vs 81.4%, p = 0.77). In conclusion, within GWTG participating hospitals, weekend/holiday staffing provides the same quality of care in ACS for discharge medications and counseling compared with full weekday staffing. However, there remain further opportunities to improve utilization of guideline-recommended therapies irrespective of discharge day.