We report here that leptin can act as a negative signal for the proliferation of human naturally occurring Foxp3⁺CD4⁺CD25⁺ regulatory T (T_reg) cells. Freshly isolated T_reg cells produced leptin and expressed high amounts of leptin receptor (ObR). In vitro neutralization with leptin monoclonal antibody (mAb), during anti-CD3 and anti-CD28 stimulation, resulted in T_reg cell proliferation, which was interleukin-2 (IL-2) dependent. T_reg cells that proliferated in the presence of leptin mAb had increased expression of Foxp3 and remained suppressive. The phenomena appeared secondary to leptin signaling via ObR and, importantly, leptin neutralization reversed the anergic state of the T_reg cells, as indicated by downmodulation of the cyclin-dependent kinase inhibitor p27 (p27^kip1) and the phosphorylation of the extracellular-related kinases 1 (ERK1) and ERK2. Together with the finding of enhanced proliferation of T_reg cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases.