This study was designed to explore the profile of immune cell subsets, including T, B, natural killer (NK), and NKT cells, in systemic lupus erythematosus (SLE) patients, and to determine their relationships with the clinical index and the effects of cyclophosphamide (CYC) and mycophenolate mofetil (MMF) treatment. SLE patients (n = 28) and age/sex-matched healthy controls (n = 28) were evaluated. The patients were equally divided into two treatment groups: intravenous drip (IVD) with CYC and prednisolone, and oral MMF and IVD with prednisolone. SLE peripheral blood samples were taken immediately prior to treatment and after 4 weeks of drug treatment. T, B, NK, and NKT cell subsets were measured by flow cytometry. Double-stranded DNA antibody and Sm antibody were detected by indirect immunofluorescence. Serum C3, C4, and C-reactive protein were determined by scatter turbidimetry. The percentages of CD3+CD4+ T, CD3-CD16CD56+ NK, and CD3+CD16CD56+ NKT cells and the CD4+/CD8+ ratio were significantly lower in SLE patients, while CD3+CD8+ T and CD3-CD19+ B cells were higher than the controls. The lymphocyte subsets were significantly correlated with the SLE disease activity index (SLEDAI) and complement factors (C3, C4). Four weeks of CYC or MMF treatment led to a significant increase in CD3+CD4+ T cells (P < 0.05). In addition, both CYC and MMF treatments led to increases in CD3+ T and CD3-CD16CD56+NKT cells and decreases in CD3-CD16CD56+ NK and CD3+CD8+ T cells, but these changes were not obvious. The significant correlation that exists between lymphocytes subsets and SLEDAI activity scores suggests that the lymphocyte subsets may reflect SLE severity. Our results indicate that both the traditional cyclophosphamide agent and the new mycophenolate mofetil agent can regulate the lymphocyte subsets and consequent abnormal immunity, suggesting that MMF, which is known to produce less side-effects than CYC, may be used as an effective treatment of SLE.