We investigated whether, in systemic lupus erythematosus (SLE), the CD45 isoforms expression on peripheral blood T-lymphocytes (T-PBL) is related to the auto-immune processes and hematological manifestations. The CD45RA/RO patterns of CD4+ and CD8 bright+ T-PBL were determined by three-colour flow cytometry. The serum levels of anti-nuclear (ANA), anti-double stranded DNA (ds DNA) and anti-cardiolipin (CL) autoantibodies were quantified by ELISA. The hematological parameters were routinely assessed. 72% of SLE patients (n = 29) had reduced lymphocyte counts, which correlated with more severe physician's assessment of disease activity, increased ANA and anti-ds DNA auto-antibodies. The lymphopenia preferentially affected the CD4+ T-PBL and, among them, the "naive" CD45RA+, RO- cells. Thus, compared with healthy women (n = 29), SLE patients had less naive and more "transient" CD45RA+, RO+ cells among CD4+ T-PBL. Meanwhile, on average, the CD45 isoforms expression on CD8+ T-PBL was unchanged. Interestingly, in 3 patients who were repeatedly evaluated, increases of transient CD8+ T-PBL paralleled the elevation of anti-ds DNA. In addition, high anti-CL was associated with more transient CD4+ and CD8+ T-PBL. The loss of naive and increase of transient CD8+ T-PBL was associated with increased disease activity and possibly hemolytic anemia. Thus, in SLE, the enhanced phenotypic switch from naive CD45RA+, RO- to "memory" CD45RO+ T-PBL patterns paralleled the auto-immune processes characteristic of this disease.