Objective. To assess whether hydroxychloroquine can delay renal damage development in lupus nephritis patients. Methods. Lupus nephritis patients (n = 256) from the LUpus in MInorities, NAture versus nurture study (n = 635), a multiethnic cohort of African Americans, Hispanics, and Caucasians, age ≥16 years with disease duration ≤5 years at baseline (T0) were studied. Renal damage was defined using the Systemic Lupus International Collaborating Clinics Damage Index (≥1 of the following lasting at least 6 months: estimated/measured glomerular filtration rate <50%, 24-hour proteinuria ≥3.5 gm and/or end-stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n = 53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potential confounders. Kaplan-Meier survival curves based on hydroxychloroquine intake or the World Health Organization (WHO) class glomerulonephritis were also derived. Results. Sixty-three (31.0%) of the 203 patients included developed renal damage over a mean ± SD disease duration of 5.2 ± 3.5 years. The most frequent renal damage domain item was proteinuria. Patients who received hydroxychloroquine (79.3%) exhibited a lower frequency of WHO class IV glomerulonephritis, had lower disease activity, and received lower glucocorticoid doses than those who did not take hydroxychloroquine. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (hazard ratio [HR] 0.12, 95% confidence interval [95% CI] 0.02-0.97, P = 0.0464) and reduced (HR 0.29, 95% CI 0.13-0.68, P = 0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in those who did not take hydroxychloroquine and those classified as WHO class IV glomerulonephritis (P < 0.0001). Conclusion. After adjusting for possible confounding factors, the protective effect of hydroxychloroquine in retarding renal damage occurrence in systemic lupus erythematosus is still evident. © 2009, American College of Rheumatology.