Determine the stage in B cell development that a Systemic Lupus Erythematosus (SLE)-associated DNA methylation signature originates in African American (AA) and European American (EA) individuals and assess its ability to predict SLE status in individual and mixed immune cells.B cells from AA (n = 31) and EA (n = 49) patients were sorted using fluorescence activated cell sorting (FACS) into five subsets. DNA methylation measured at ~460,000 CpG sites was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE-associated methylation sites was performed. A random forest algorithm identified an epigenetic signature of SLE in the B cell subsets, which validated in an independent cohort.Regression analysis across all B cell stages resulted in 60 CpGs that reached genome-wide significance (p ≤ 1.07x10 ). Interrogation of ethnicity-specific CpGs associated with SLE revealed a hypomethylated pattern enriched for interferon-regulated genes and EBF1 binding (p < 0.001) in AA patients. Predictive models developed in the transitional B cell subset distinguished AA SLE patients from controls when applied to other B cell subsets (mean ROC-AUC = 0.98), as well as CD19+ pan-B cells (ROC-AUC = 0.95) and CD4+ pan-T cells (ROC-AUC = 0.97) from an independent cohort.Our results indicate that SLE-specific methylation patterns are ethnicity dependent. Epigenetic changes near interferon-regulated genes early in B cell development is a hallmark of SLE in AA females. EBF1 binding sites are highly enriched for significant methylation changes, nominating it as a potential regulator of SLE-associated epigenetic changes. This article is protected by copyright. All rights reserved.