Objective. To determine whether receptors for B lymphocyte stimulator (BLyS) are altered on B cells of patients with systemic lupus erythematosus (SLE). Methods. Total available receptors for BLyS were measured by analysis of binding of recombinant soluble BLyS to peripheral blood B cells in 36 SLE patients, 29 healthy controls, and 10 disease controls. Antibodies to the receptors BAFF-R, BCMA, and TACI were used to define expression of the individual BLyS receptors on subsets of B cells in blood, spleen, and tonsils. Two different antibodies to BAFF-R, which were differentially sensitive to BAFF-R occupancy, were used to compare BAFF-R on B cells in an additional 20 healthy subjects and 25 SLE patients. Assays of B cell survival after stimulation in vitro were used to determine the sensitivity of B cells to exogenous BLyS. Results. Total available receptors for BLyS were decreased in patients with SLE, independent of changes of subsets in the blood in these patients. The decrease correlated with changes in disease activity. Although total surface BAFF-R was not significantly different between healthy controls and SLE patients, BAFF-R was occupied in SLE patients. B cells from these patients were less responsive to exogenous BLyS. Conclusion. BAFF-R is consistently occupied on blood B cells in SLE. Occupancy of BAFF-R on blood B cells is likely to contribute to disease mechanisms in SLE and could serve as a biomarker of disease activity. Targeting BLyS as a therapeutic strategy will require overcoming the persistent binding of BLyS to BAFF-R. © 2005, American College of Rheumatology.