BackgroundThe inverse association between physical activity and cardiovascular disease (CVD) is well‐ established and has previously been shown in people with and without single CVD risk factors. We examined whether level of global cardiovascular risk, on the basis of the pooled cohort equation or Reynolds risk score, which include multiple risk factors, modified the physical activity–CVD association.Methods and ResultsParticipants in the prospective WHS (Women's Health Study; n=27 536) reported their leisure‐time physical activity at study entry (1992–1995) and during follow‐up through 2013. Participants were divided into 10‐year cardiovascular risk groups on the basis of the pooled cohort equation and Reynolds risk score. The primary outcome was incident total CVD. The CVD hazard ratio for active (≥500 kcal/wk of physical activity) compared with inactive (<500 kcal/wk) individuals was 0.73 (95% confidence interval, 0.66–0.80) in multivariable models. This association was not modified by level of cardiovascular risk; physical activity was inversely associated with CVD within all pooled cohort equation and Reynolds risk score groups (P=0.17 and P=0.66 for interaction, respectively). When the joint association of physical activity and level of cardiovascular risk was examined, women with higher risk on the basis of either the pooled cohort equation or Reynolds risk score had higher CVD rates compared with those at low risk, regardless of physical activity. However, among women at both high and low risk, being physically active was associated with lower risk of CVD events.ConclusionsIn this large prospective cohort of women, level of global cardiovascular risk did not modify the inverse association between leisure‐time physical activity and incident CVD. Thus, promoting physical activity is important in women at both low and high cardiovascular risk.