Coronary heart disease (CHD) is more common in men than women. Gender differences in CHD risk may be explained by a different impact that coronary risk factors may have for men and women, in the development of CHD. Thus, the authors aimed to analyze the extent to which cardiovascular risk factors can explain the gender difference in CHD risk, at population level. During 2000-2001, 848 hospitalized patients with a first event of acute coronary syndrome and 1078 controls, paired by gender, age, and region with no evidence of overt CHD, were randomly selected from all Greek regions. Data revealed that women experiencing their first acute coronary syndrome were significantly older than men (65.3+/-8 vs. 59.7+/-10 years old; p<0.01), and that acute coronary syndrome occurred more frequently in men than women (frequency ratio 4:1, men:women). When adjusting for age, multivariate analysis revealed that both family history of premature CHD and hypercholesterolemia were associated with higher coronary risk in men than women (odds ratio [OR]=5.11 vs. 3.14; p<0.05 for family history and OR=3.77 vs. 2.19; p<0.05 for hypercholesterolemia). The presence of hypertension however, had a significantly greater effect in women than men (OR=4.86 vs. 1.66; p<0.01). Also, higher education level and the adoption of a Mediterranean diet had a more protective effect in women than men (OR=0.53 vs. 0.87; p<0.001; and OR=0.80 vs. 0.96; p<0.05, respectively). There was also evidence of a greater association between depression and higher coronary risk in women than men (OR=1.93 vs. 1.58; p<0.07). The impact of other factors (i.e., smoking, diabetes, body mass index, physical activity, alcohol consumption, and financial status), on the coronary risk difference between genders was similar for men and women. In conclusion, our findings suggest that the contribution of certain coronary risk factors to the risk for CHD is different for men and women.