CD4⁺ T cells are important in adaptive immunity, but their dysregulation can cause autoimmunity. Here we demonstrate that the multifunctional adaptor protein β-arrestin 1 positively regulated naive and activated CD4⁺ T cell survival. We found enhanced expression of the proto-oncogene Bcl2 through β-arrestin 1–dependent regulation of acetylation of histone H4 at the Bcl2 promoter. Mice deficient in the gene encoding β-arrestin 1 (Arrb1) were much more resistant to experimental autoimmune encephalomyelitis, whereas overexpression of Arrb1 increased susceptibility to this disease. CD4⁺ T cells from patients with multiple sclerosis had much higher Arrb1 expression, and 'knockdown' of Arrb1 by RNA-mediated interference in those cells increased apoptosis induced by cytokine withdrawal. Our data demonstrate that β-arrestin 1 is critical for CD4⁺ T cell survival and is a factor in susceptibility to autoimmunity.