Recently, the focus of research on cardiovascular risk factors has broadened because of new data demonstrating benefits of low risk (i.e., favorable) levels of all major modifiable risk factors. Most data on low risk relate to coronary heart disease, not stroke. This population-based, 12-sample, Italian study (Progetto CUORE, 1983-2002), with 10-year follow-up, assessed the relation of low risk to stroke and implications for prevention. At baseline, women and men were 35-69 years of age. Only 3% were low risk; 80% were high risk. Overall, stroke incidence rates were 20.7 for men and 9.6 for women per 10,000 person-years. No strokes occurred in low risk participants, and stroke incidence was low with borderline elevation of only one risk factor. Four modifiable risk factors--elevated blood pressure, smoking, diabetes, and high total cholesterol/high density lipoprotein cholesterol ratio--related independently to stroke risk. For those at low risk or who had only one unfavorable (but not high) risk factor, the stroke rate was 76% lower than for high risk participants; for all persons not at high risk, the stroke rate was 57% lower than for those at high risk. Results show that favorable risk factor levels assure minimal stroke risk. Population-wide prevention is needed, especially improved lifestyles, to increase the prevalence of low risk.