Recently, there has been an awareness of the variable phenotypic expression of numerous disorders between individuals from different ethnicities, systemic lupus erythematosus (SLE) one of them. These disparities probably arise from the interaction between genetic and non-genetic (environmental, socioeconomic-demographic, cultural and behavioral) factors. To delineate the influence of these factors on SLE outcome, we established a multiethnic (Hispanic, African American and Caucasian) United States (US) early cohort (<5 years disease duration). Ten years later, interesting data have emerged from the LUMINA (Lupus in Minorities: Nature vs. nurture) cohort. For example, African Americans and Hispanics from Texas have a more severe disease than Caucasians and Hispanics from Puerto Rico. Lack of private insurance, acute SLE onset, expression of HLA-DRB1*01 (DR1) and C4A*3 alleles were associated with higher disease activity, whereas age, the number of American College of Rheumatology criteria met, disease activity, corticosteroid use and abnormal illness behaviors were consistent predictors of damage. In turn, damage and poverty were found to predict mortality. We now plan to apply new approaches (genetic admixture) to deconfound the complex interaction between genetic and non-genetic factors influencing SLE outcome. These data may have impact on the development of policies aimed at eliminating health disparities in the US.