OBJECTIVE: Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular disease. However, prospective population-based data addressing this association have been lacking. METHODS: We conducted a prospective cohort study among 119,332 women participating in the Nurses' Health Study who were free of cardiovascular disease and SLE at baseline in 1976. Incident SLE was confirmed by medical record review. Cardiovascular events included fatal and nonfatal myocardial infarction, stroke, coronary artery bypass grafting, and angioplasty. The relative risk (RR) of cardiovascular events among participants with SLE as compared with those without SLE was estimated using Cox proportional hazards models. RESULTS: Over 28 years of followup (2.9 million person-years), 8,169 cardiovascular events occurred and 148 women developed incident SLE. The mean age at SLE diagnosis was 52.6 years, and 20 participants with SLE developed a subsequent cardiovascular event. After adjusting for potential confounding factors, including age, race, cardiovascular risk factors, and medication use, the RR of a cardiovascular event in women with SLE compared with those without SLE was 2.26 (95% confidence interval [95% CI] 1.45-3.52). When end points were analyzed separately, the RR for coronary heart disease was 2.25 (95% CI 1.37-3.69) and the RR for stroke was 2.29 (95% CI 0.85-6.15). CONCLUSION: In this prospective population-based study, we found a statistically significant >2-fold increased risk of cardiovascular disease among participants with SLE. The risk was not as high as has been previously reported, which may have been due to the relatively high age at diagnosis of SLE in this cohort.