The 5-year incidence of cardiovascular disease (CVD) and its determinants, in a sample of men and women from Greece, was evaluated. From May 2001 to December 2002, 1514 men and 1528 women (>18 years old) without any clinical evidence of CVD, living in the Attica area, Greece, were enrolled in the ATTICA study. In 2006, a group of experts performed the 5-year follow-up (941 of the 3042 (31%) participants were lost to follow-up). Development of CVD (coronary heart disease, acute coronary syndromes, stroke, or other CVD) during the follow-up period was defined according to WHO-ICD-10 criteria. The 5-year incidence of CVD was 11.0% in men and 6.1% in women (p<0.001); the case fatality rate was 1.6%. Multi-adjusted logistic regression analysis revealed that increased age (odds ratio per year=1.09, p=0.04), waist-to-hip ratio (odds ratio=5.07, p=0.02), hypertension (odds ratio=4.53, p=0.001), diabetes (odds ratio=4.53, p=0.001) and C-reactive protein levels (odds ratio per 1 mg/dl=1.31, p=0.02) were the most significant baseline bio-clinical predictors of CVD. Furthermore, an increased education level and greater adherence to the Mediterranean diet (among 35-65-year-old individuals) were associated with a lower CVD incidence (odds ratio per 3 years of school difference=0.83, p<0.001 and odds ratio per 1/55 units in diet score=0.94, p<0.001), irrespective of various potential confounders. In conclusion, aging, central fat, hypertension and diabetes, inflammation process, low social status and abstinence from a Mediterranean diet seem to predict CVD events within a 5-year period.