The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57±0.24%, n= 45 vs 1.29±0.38%, n= 82, p< 0.0001) or with inactive patients (1.22±0.67%, n= 62, p< 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls’ values (1.15±0.46%, n= 21, p= 0.09 and 1.16±0.44%, n= 16, p= 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.