OBJECTIVE: We evaluated the effects of the BAFF targeting antibody, Belimumab, on human nonmemory B cell pools. Human B cell pools were identified using surface markers adapted from mouse studies that specifically assessed reductions in immature B cells due to BAFF-depletion. SLE patients have high levels of both BAFF and immature B cells. Mechanistic mouse studies provide a framework for understanding human responses to therapies that target B cells. METHODS: PBMCS were isolated from healthy donors and SLE patients on Belimumab or standard-of-care therapy (SCT). Cells were stained for flow cytometry to identify B cell subsets based on CD21/CD24. Differences in subset proportions were determined by one way ANOVA and Tukey’s post hoc test. RESULTS: Patients treated with Belimumab show alterations in the nonmemory B cell pool characterized by a decrease in the Transitional 2 (T2) subset (p=0.002), and an increase in the proportion of Transitional 1 (T1) cells (p=0.005) as compared to healthy donors and SCT patients. The naïve B cell compartment showed no significant differences between the groups (p = 0.293). CONCLUSION: Using a translational approach, we show that Belimumab-mediated BAFF-depletion reduces the T2 subset in patients, similar to observations in mouse models with BAFF-depletion.