Background: The age-standardized death rates under 65 years from ischemic heart disease in South Eastern Europe are approximately twice as high than the Western Europe average, but the reasons are not completely recognized. The aim of the present study was to address this issue by collecting and analyzing data from a large, multinational cohort. Methods: We enrolled 70,953 Caucasian patients with first acute coronary syndrome, from 36 urban hospital in 7 South Eastern European countries and assessed their life expectancy free of acute coronary syndrome and mortality within 30 days after hospital admission from acute coronary syndrome as estimated in relation to dichotomous categories of traditional risk factors (current smoking, hypertension, diabetes and hypercholesterolemia) stratified according to sex. Findings: Compared with patients without any baseline traditional risk factors, the presence of all four risk factors was associated with a 5-year shorter life expectancy free of acute coronary syndrome (women: from 67.1 ± 12.0 to 61.9 ± 10.3 years; r = -0.089; p < 0.001 and men: from 62.8 ± 12.2 to 58.9 ± 9.9 years; r = -0.096; p < 0.001). Premature acute coronary syndrome (women <67 years and men <63 years) was remarkably related to current smoking and hypercholesterolemia among women (RRs: 3.96; 95% CI: 3.72-4.20 and 1.31; 95% CI: 1.25-1.38, respectively) and men (RRs: 2.82; 95% CI: 2.71-2.93 and 1.39; 95% CI: 1.34-1.45, respectively). Diabetes was most strongly associated with death from premature acute coronary syndrome either in women (RR: 1.52; 95% CI: 1.29-1.79) or men (RR: 1.63; 95% CI: 1.41-1.89). Interpretation: Public health policies in South Eastern Europe should place significant emphasis on the four traditional risk factors and the associated lifestyle behaviors to reduce the epidemic of premature ischemic heart disease.