The study was promoted to probe into the effect of BLyS on the activity of peripheral B lymphocytes mediated by BLyS receptors in patients with systemic lupus erythematosus (SLE). Thirty new-onset patients having fulfilled the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE. Twenty age-matched healthy volunteers were recruited for this study. Peripheral blood samples were used to analyze the expression of BLyS protein and related receptors (BR3, TACI), to detect peripheral B cell subpopulations of different phases. Clinical disease activity was evaluated according to the systemic lupus erythematosus disease activity index (SLEDAI-2000). The percentage of CD19(+)CD5(+), CD19(+)CD27(+), CD19(+)CD38(+) and total CD19(+) in the peripheral blood is significantly higher in SLE patients than that in healthy controls (p < 0.01). BLyS concentrations and TACI expression are up-regulated in SLE patients (p < 0.01) while BR3 showed no differences between the two groups (p > 0.05). BLyS concentrations and TACI MFI both showed positive correlation with SLEDAI (r(2) = 0.391, p < 0.001, r(2) = 0.339, p = 0.001), whereas BR3 expression showed no relationship with SLEDAI. The disorders of peripheral B cell subsets maybe reflect the effect of BLyS on the activity of peripheral B lymphocytes mediated by BLyS receptors. The significant up-regulation of BLyS and its receptors, especially TACI may serve as a target for the treatment of SLE.