Background: Substantial sex differences exist in the incidence of cardiovascular disease (CVD), with women at lower risk for coronary heart disease (CHD) but higher risk for stroke compared with men. However, the underlying reasons remain poorly understood, and no study to date has quantified the contribution of conventional cardiovascular risk factors to these sex differences. Methods: We prospectively followed 71,342 women from the Nurses’ Health Study and 36,499 men from the Health Professionals Follow-up Study (1986-2012) without CVD history at baseline who had complete data on Life’s Simple 7 (LS7), including smoking, diet quality, physical activity, body mass index (BMI), hypertension, hypercholesterolemia and diabetes. Time-varying Cox proportional hazards regression was used to estimate hazard ratios (HRs) for CHD and stroke comparing men versus women adjusted for age. Impact of LS7 on sex differences was evaluated by change in the sex HR estimate after further adjustment for LS7. We assessed effect modification by sex for the associations between individual components of LS7 and risk of CHD and stroke. Results: The age-adjusted HR (95% CI) comparing men versus women was 2.21 (2.10, 2.32) for CHD and 0.74 (0.69, 0.80) for stroke. Rates of achieving LS7 goals were in general worse among women compared to men (age-standardized mean LS7 score: 3.7 versus 4.1). Smoking, diabetes, hypertension and hypercholesterolemia were more strongly associated with CHD risk in women than in men (p-interaction<0.01), whereas the associations with BMI, diet quality and physical activity were similar by sex (p-interaction>0.23). For example, every 5 pack-years of smoking was associated with 19% higher CHD risk in women (95% CI: 1.17, 1.21) and 8% higher risk in men (95% CI: 1.06, 1.10). The HR (95% CI) associated with diabetes was 2.63 (2.40, 2.88) in women and 1.32 (1.15, 1.50) in men. By contrast, while most risk factors showed stronger associations with stroke risk in women than in men, only the difference for smoking reached statistical significance (p-interaction=0.009). After adjustment for LS7, the HR (95% CI) by sex increased to 2.61 (2.47, 2.75) for CHD and was attenuated to 0.83 (0.76, 0.89) for stroke. Conclusion: Lower LS7 achievement and stronger associations of LS7 with CVD outcomes in women than in men appeared to explain some of the sex difference in stroke risk but not CHD risk on the risk ratio scale. Ongoing work is exploring the impact of LS7 on sex differences on the absolute risk difference scale.