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Lymphopenia is a common clinical manifestation in patients with systemic lupus erythematosus (SLE). However, its physiopathogenic role and the contribution of different T cell subsets in this setting have not been addressed fully. The aim of this study was to characterize T cell subsets quantitatively and functionally and their association with lymphopenia and azathioprine treatment in SLE. We included 84 SLE patients and 84 healthy controls and selected 20 patients for a 6-month longitudinal analysis. Peripheral blood mononuclear cells were isolated, and T cell subsets were analysed by flow cytometry. Functional analyses included autologous and allogeneic co-cultures of T cells. Our data show persistently lower absolute numbers of CD4+CD25high T cells [regulatory T cells (Tregs)] (1·9 versus 5·2, P < 0·01) and CD4+CD69+ T cells (3·2 versus 9·3, P = 0·02) and higher activity scores (4·1 versus 1·5, P = 0·01) in SLE patients with lymphopenia compared with those without lymphopenia. Lymphopenia increased the risk for decreased numbers of CD4+CD25high cells (relative risk 1·80, 95% confidence interval 1·10–2·93; P = 0·003). In addition, azathioprine-associated lymphopenia was characterized by decreased absolute numbers of CD4+CD69+ and CD4+interleukin (IL)-17+ cells compared to disease activity-associated lymphopenia. Functional assays revealed that SLE effector T cells were highly proliferative and resistant to suppression by autologous Tregs. In summary, lymphopenia was associated with deficient numbers of CD4+CD25high and CD4+CD69+ cells and resistance of effector T cells to suppression by Tregs, which could contribute to the altered immune responses characteristic of SLE. Furthermore, azathioprine treatment was associated with decreased numbers of CD4+CD69+ and CD4+IL-17+ cells and diminished Treg suppressive activity.