Human CD4⁺CD25^highCD127⁻FoxP3⁺ regulatory T (T_reg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral T_reg cells has been previously reported in autoimmune disorders^,. T_reg cells represent the most actively replicating compartment within the CD4⁺ cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state^,. Here we report that proliferation of T_reg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)–signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27^kip1) and extracellular signal–related kinases 1 and 2 (ERK1/2). The impaired capacity of T_reg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in T_reg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of T_reg cells in autoimmune disease.