Objective. To determine the differences in clinical manifestations, disease activity, damage accrual, and medication use in systemic lupus erythematosus (SLE) patients as a function of menopausal status at disease onset. Methods. Women with SLE as per the criteria of the American College of Rheumatology, with disease duration of ≤5 years and of Hispanic (Texas and Puerto Rico ancestries), African American, and Caucasian ethnicity, from LUMINA (LUpus in Minorities, NAture versus nurture), a multiethnic, longitudinal cohort, were studied. Menopause at the time of disease onset was defined as self-report of climacteric symptoms, and/or amenorrhea lasting >6 months, and/or oophorectomy, and/or increased follicle-stimulating hormone values for reproductive-age women, and/or treatment with hormone replacement therapy. Patients were divided into premenopausal and postmenopausal categories. Socioeconomic status, cumulative clinical manifestations, disease activity (at study entry or time 0, last visit, and over time), as measured by the Systemic Lupus Activity Measure, and damage accrual, as measured by the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology damage index (at time 0 and at last visit) were compared between the 2 groups of women. Multivariable models were then examined making adjustments for all possible known confounders. Dependent variables in the models were renal involvement, damage accrual, arterial vascular events, and venous thrombosis. Results. Five hundred eighteen women from the LUMINA cohort were included; 436 (84.2%) were premenopausal and 82 (15.8%) were postmenopausal. Disease onset after menopause was more common among Caucasians. Renal involvement was more common in premenopausal women, whereas vascular arterial events were more frequent in postmenopausal women. All other disease manifestations, as well as disease activity, were comparable between both groups. The presence of damage accrual at time 0 and study end was more frequent in postmenopausal women. Age, rather than menopausal status, independently contributed to damage accrual, renal involvement, and vascular arterial events in these women. Conclusion. A hypoestrogenemic state secondary to menopause appears not to be protective against disease activity and damage accrual. Age rather than menopausal status is a strong independent predictor of damage accrual and of vacular events in women with lupus. © 2005, American College of Rheumatology.