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 < or = 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.