Aims: To examine the effect that within-person variation has on the estimated risk associations between cigarette smoking, physical inactivity, and increased body mass index(BMI) and the development of cardiovascular disease(CVD) in middle aged Britishmen. Methods and results: In total, 6452 men aged 40-59 with no prior evidence of CVD were followed for major CVD events(fatal/non-fatal myocardial infarction or stroke)and all-cause mortality over 20 years; lifestyle characteristics were ascertained at regular points throughout the study. A major CVD event within the first 20 years was observed in 1194 men(18.5%). Use of baseline assessments of cigarette smoking and physical activity in analyses resulted in underestimation of the associations between average cumulative exposure to these factors and major CVD risk. After correction for within-person variation, major CVD rates were over four times higher for heavy smokers(≥40 cigarettes/day) compared with never smokers and three times higher for physically inactive men compared with moderately active men. Major CVD risk increased by 6%for each 1 kg/m2 increase in usual BMI. If all men had experienced the risk levels of the men who had never regularly smoked cigarettes, were moderately active, and had a BMI of ≤25 kg/m2(6%of the population), 66%of the observed major CVD events would have been prevented or postponed(63%before adjustment for within-person variation). Adjustment for a range of other risk factors had little effect on the results. Similar results were obtained for all-cause mortality. Conclusion: Failure to take account of within-person variation can lead to underestimation of the importance of lifestyle characteristics in determining CVD risk. Primary prevention through lifestyle modification has a great preventive potential. Aims: To examine the effect that within-person variation has on the estimated risk associations between cigarette smoking, physical inactivity, and increased body mass index (BMI) and the development of cardiovascular disease (CVD) in middle aged Britishmen. Methods and results: In total, 6452 men aged 40-59 with no prior evidence of CVD were followed for major CVD events (fatal / non-fatal myocardial infarction or stroke) and all-cause mortality over 20 years; lifestyle characteristics were ascertained at regular points throughout the A major CVD event within the first 20 years was observed in 1194 men (18.5%). Use of baseline assessments of cigarette smoking and physical activity in analyzing leads in underestimation of the associations between average cumulative exposure to these factors and major CVD risk After correction for within-person variation, major CVD rates were over four times higher for heavy smokers (≥40 cigarettes / day) compared with never smokers and three times hi gher for physically inactive men compared with moderately active men. Major CVD risk increased by 6% for each 1 kg / m2 increase in usual BMI. If all men had experienced the risk levels of the men who had never regularly smoked cigarettes, were moderately active , and had a BMI of ≤25 kg / m2 (6% of the population), 66% of the observed major CVD events would have been prevented or postponed (63% before adjustment for within-person variation). Adjustment for a range of other results are all for cause mortality. Conclusion: Failure to take account of within-person variation can lead to underestimation of the importance of lifestyle characteristics in determining CVD risk. Primary prevention through lifestyle modification has a great preventive potential.