AIMS: Better understanding of sex differences in cardiovascular disease (CVD) is essential in tailoring appropriate preventative strategies. Using a large population-based study with follow-up >25 years, we aimed to determine sex-specific lifetime risks of incident CVD and cardiovascular (CV) mortality amongst populations with and without prevalent CVD. METHODS AND RESULTS: Participants were drawn from the European Prospective Investigation into Cancer-Norfolk and followed up for a median of 26.2 years. Sex-specific lifetime risks were ascertained accounting for the competing risk of death. Models were adjusted for ethnicity and time-updated covariates: material deprivation, CV risk factors, lifestyle factors, comorbidities, and medication. A total of 23 859 participants [54.5% women; mean age (standard deviation) 59.2 (9.3) years at baseline] were included. Adjusted lifetime risks of incident CVD were higher in men than in women (69.1 vs. 57.7% at age 75): cause-specific hazard ratio (cHR) (99% confidence interval)-1.49 (1.41-1.57), while the risks of CV mortality at age 75 were 4.4% (men) and 3.1% (women): cHR-1.42 (1.31-1.54). Myocardial infarction was the predominant first presentation in men until the eighth decade. In women, the first CVD manifestations after their sixth decade were predominantly atrial fibrillation and stroke. The male-associated excess relative risks of incident CVD and CV mortality were halved in people with prevalent CVD. CONCLUSION: We characterized the sex-specific lifetime CV risks in a large cohort. Men had substantially higher risk of incident CVD and CV mortality than women, which was attenuated amongst people with prevalent CVD. Our findings provide an evidence base for sex-specific CV prevention.