Upon activation, a subset of mature human CD8+ T cells re-expresses CD4 dimly. This CD4dimCD8bright T cell population is genuine and enriched in antiviral CD8+ T cell responses. The signaling pathway that leads to CD4 re-expression on mature CD8+ T cells is not clear. Given that Wnt/β-catenin signaling plays a critical role in the transition of CD4-CD8- to CD4+CD8+ thymocytes, we determined whether β-catenin mediates CD4 expression on mature CD8+ T cells. We demonstrate that active β-catenin expression is 20-fold higher on CD4dimCD8 bright than CD4-CD8+ T cells. Activation of β-catenin signaling, through LiCl or transfection with a constitutively active construct of β-catenin, induced CD4 on CD8+ T cells by ∼10-fold. Conversely, inhibition of β-catenin signaling through transfection with a dominant-negative construct for T cell factor-4, a downstream effector of β-catenin signaling, diminished CD4 expression on CD8+ T cells by 50% in response to T cell activation. β-catenin-mediated induction of CD4 on CD8+ T cells is transcriptionally regulated, as it induced CD4 mRNA, and T cell factor/lymphoid enhancer factor sites were identified within the human CD4 promoter. Further, β-catenin expression induced the antiapoptotic factor BcL-xL, suggesting that β-catenin may mediate protection against activation-induced cell death. Collectively, these data demonstrate that β-catenin is critical in inducing CD4 expression on mature CD8+ T cells, suggesting that it is a common pathway for CD4 upregulation among thymocytes and mature CD8 + T cells.