We assessed the effect of previous peripheral arterial disease (PAD) and stroke on clinical outcomes in patients with acute coronary syndrome (ACS) and sought to ascertain the effectiveness of evidence-based therapies in these patients. We used data from the multinational Global Registry of Acute Coronary Events. Patients were enrolled at 102 hospitals in 13 countries between April 1999 and September 2005. Patients presenting with ACS were stratified according to the presence of previous PAD, stroke, PAD and stroke, or neither. In-hospital analysis included 48,418 patients and 6-month analysis included 32,735 patients. The primary end point was all-cause mortality and major adverse cardiac events during 6-month follow-up. Adverse in-hospital and 6-month events were lowest in patients with neither PAD nor stroke and highest in patients with PAD and stroke after adjustment for baseline demographics and co-morbidities. In-hospital mortality for the 4 groups (neither, PAD, stroke, PAD and stroke) was 4.5% versus 7.2% versus 8.9% versus 9.4% (p <0.001) and that for 6-month mortality was 3.9% versus 8.8% versus 9.3% versus 12%, and these differences persisted after accounting for differences in baseline characteristics. Use of evidence-based therapies was associated with significantly less morbidity and mortality in all ACS subgroups. In conclusion, outcomes after ACS are worse in patients with PAD or stroke, with the highest risk in patients with the 2 conditions and the use of evidence-based therapies are associated with improved outcomes in all ACS subgroups.