Objective The aim of this study was to evaluate the changes in CD8+CD28–/CD8+CD28+ T-cell subset balance and in the CD8+CD28– Treg cell number and function in patients with systemic lupus erythematosus (SLE). Methods Cell isolation and flow cytometry analysis were employed to investigate the T-cell subsets. Results It was found that in high-activity SLE patients, the CD8+CD28+ T-cell subset was reduced, which was inversely correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and that the CD8+CD28–/CD8+CD28+ ratio was elevated, which was positively correlated with SLEDAI and with renal damage and inversely correlated with serum complement level, whereas the CD8+CD28– T-cell subset was increased only in inactive patients. It was also found that apoptosis of CD8+ T cells increased, and Fas, Fas ligand (FasL) and interleukin (IL)-6 expression were high, whereas cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) expression was low by the CD8+CD28+ T cell subset in active SLE patients; apoptosis was positively correlated with SLEDAI and with the expression of Fas and FasL by the CD8+CD28+ T-cell subset in active SLE patients. IL-6 and CTLA-4 expression were found to be low by the CD8+CD28– T cell subset in active SLE patients. Conclusion These data suggest that high expression of Fas, FasL and IL-6 and low expression of CTLA-4 by the CD8+CD28+ T-cell subset promotes the activation-induced cell death of the CD8+CD28+ T-cell subset, resulting in an imbalance of CD8+CD28–/CD8+CD28+ T cells in active SLE patients, which represents an important feature in the immunological pathogenesis of SLE. The CD8+CD28– T-cell subset may play some role in inactive SLE.