Guidelines for primary prevention recommend calculation of lifetime risk for cardiovascular disease (CVD) in addition to short-time risk. We aimed at evaluating the distribution of CVD lifetime risk and the percentage of Italians having low short-term, but high lifetime, risk. Cross-sectional general population-based cohort study. We included 8,403 (46% men) cardiovascular disease-free individuals aged 35-50 years, among those randomly recruited in the framework of the MOLI-SANI cohort. Participants were stratified into three groups: low short-time (10-year) (≤3% and non diabetic)/low lifetime, low short-time/high lifetime, and high short-time risk. Short-time risk was evaluated by the equation provided by the Italian CUORE project. Lifetime risk was evaluated using the algorithm derived from the Framingham cohort. High short-time risk was prevalent in 16% population (32% of men and 2% of women). Among individuals with low short-time risk, 80% had high lifetime risk (82% men and 78% women). The proportion of individuals with very low lifetime risk due to all optimal risk factors was 4.1% only (1.5% men and 6.3% women). A large proportion of Italian adults not qualified for CVD primary prevention because of their very low short-time predicted CVD risk, are in fact at high risk to develop a CVD event in their lifetime; therefore population-based approaches should be sought to modify the overall distribution of individual risk factors. These findings offer helpful information for policy makers involved in contrasting the burden of CVD, especially in women and young men.