Objective: To examine the role of ethnicity and the use of anti-malarials (protective) on lupus renal disease. Methods: A nested case-control study (1:2 proportion, n = 265 and 530) within GLADEL's (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort was carried out. The end-point was ACR renal criterion development after diagnosis. Cases and controls were matched for follow-up time (end-point or a comparable time, respectively). Renal disease predictors were examined by univariable and multivariable analyses. Additional analyses were done to determine if the protective effect of anti-malarials persisted after adjusting for intake-associated confounders. Results: Of the cases, 233 (87.9%) were women; their mean (s.d.) age at diagnosis was 28.0 (11.9) years and their median (Q3-Q1 interquartile range) follow-up time for cases and controls was 8.3 months (Q3-Q1: 23.5); 56.6% of the cases and 74.3% of the controls were anti-malarial users. Mestizo ethnicity [odds ratio (OR) 1.72, 95% CI 1.19, 2.48] and hypertension (OR 2.26, 95% CI 1.38, 3.70) were independently associated with a higher risk of renal disease, whereas anti-malarial use (OR 0.39, 95% CI 0.26, 0.58), older age at disease onset (OR 0.98, 95% CI 0.96, 0.99) and female gender (OR 0.56, 95% CI 0.32, 0.99) were negatively associated with such occurrence. After adjusting for variables associated with their intake, the protective effect of anti-malarials on renal disease occurrence persisted (OR 0.38, 95% CI 0.25, 0.58). Conclusion: Mestizo patients are at increased risk of developing renal disease, whereas anti-malarial use protects patients from such an occurrence. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.