Objective. To examine the clinical differences and the type and extent of organ damage in late- versus early-onset systemic lupus erythematosus (SLE). Methods. A nested case-control study was performed in the context of LUMINA (LUpus in MInorities, NAture versus nurture), a large, longitudinal, multiethnic cohort. Patients who developed SLE at or after the age of 50 years were considered cases. Two controls (patients who developed SLE at age ≤49 years) per case, matched for sex and disease duration, were randomly chosen. Selected baseline socioeconomic/demographic, behavioral, and psychological features, self-reported quality of life, and cumulative clinical data (clinical manifestations, laboratory data, disease activity, damage, and mortality) were compared between cases and controls. Multivariable analyses with late-onset lupus, damage accrual, and mortality as dependent variables were then performed. Results. Two hundred seventeen patients were studied. Of them, 73 were cases. Cases were more likely to have neurologic involvement, arterial thrombotic events, osteoporosis, and hypertriglyceridemia, while renal involvement and anti-Sm antibodies were less frequent. Disease activity at baseline was lower among cases. Cases also exhibited more cardiovascular and ocular damage. Late-onset lupus was an independent predictor of damage accrual (t-test = 2.23, P = 0.028), any damage at last visit (odds ratio [OR] 23.32, 95% confidence interval [95% CI] 3.98-141.56) (P < 0.001), and mortality (OR 10.74, 95% CI 3.07-37.56) (P < 0.001). Conclusion. Patients with late-onset lupus exhibit distinct clinical features. Although disease activity tends to be lower in these patients, they tend to accrue more damage and experience higher mortality than patients with early-onset lupus. These findings probably reflect the contribution exerted by other comorbid conditions in the overall impact of lupus in these patients. © 2006, American College of Rheumatology.