Randomized evidence for aspirin in the primary prevention of cardiovascular disease (CVD) among women is limited and suggests at most a modest effect for total CVD. Lack of compliance, however, can null-bias estimated effects. We used marginal structural models (MSMs) to estimate the etiologic effect of continuous aspirin use on CVD events among 39,876 apparently healthy female health professionals aged 45 years and older in the Women's Health Study, a randomized trial of 100 mg aspirin every other day versus placebo. As-treated analyses and MSMs controlled for time-varying determinants of aspirin use and CVD. Predictors of aspirin use differed by randomized group and prior use and included medical history, CVD risk factors, and intermediate CVD events. Previously reported intent-to-treat analyses found small non-significant effects of aspirin on total CVD (hazard ratio (HR) = 0.91, 95 % confidence interval (CI) = 0.81-1.03) and CVD mortality (HR = 0.95, 95 % CI = 0.74-1.22). As-treated analyses were similar for total CVD with a slight reduction in CVD mortality (HR = 0.88, 95 % CI = 0.67-1.16). MSMs, which adjusted for non-compliance, were similar for total CVD (HR = 0.93; 95 % CI: 0.81, 1.07) but suggested lower CVD mortality with aspirin use (HR = 0.76; 95 % CI: 0.54, 1.08). Adjusting for non-compliance had little impact on the estimated effect of aspirin on total CVD, but strengthened the effect on CVD mortality. These results support a limited effect of low-dose aspirin on total CVD in women, but potential benefit for CVD mortality.