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The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity.Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27(kip1), and deletion of p27(kip1) in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4(+) T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.