OBJECTIVE Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors, and SLE disease-related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE. METHODS Data were derived from 663 adult participants in the 2004-2008 Lupus Outcomes Study, who were followed for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used to determine predictors of the development of increased depressive symptom severity over a 12-month period (Center for Epidemiologic Studies Depression Scale [CES-D] score of 23 or greater), yielding 2,224 paired observations. Predictors included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke or myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking status, and family history), and SLE-specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity). RESULTS The annual incidence of depression was 12% in this cohort. Multivariate predictors of new-onset depression included younger age (ages 20-39 years: odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.3-3.9; ages 40-59 years: OR 1.8, 95% CI 1.1-2.7), Hispanic/Latino ethnicity (OR 1.8, 95% CI 1.2-2.8), having some college education (OR 1.8, 95% CI 1.1-3.0), baseline CES-D score (OR per point 1.1, 95% CI 1.1-1.2), presence of diabetes mellitus (OR 1.8, 95% CI 1.1-2.8), and baseline SLE disease activity (OR 1.2, 95% CI 1.1-1.4). CONCLUSION These results suggest that, in addition to known sociodemographic factors, the presence of diabetes mellitus and SLE disease activity may play a role in the development of depression in SLE.