Stimulation of the T cell receptor (TCR) complex initiates multiple signaling cascades that lead to the activation of several transcription factors, including the NF-kappa B family members. Although various proximal signaling components of the TCR have been intensively studied, the distal components that mediate TCR-induced NF-kappa B activation remain largely unknown. Using a somatic mutagenesis approach, we cloned a CARMA1-deficient T cell line. Deficiency in CARMA1 (originally known as CARDII) resulted in selectively impaired activation of NF-kappa B induced by the TCR and a consequent defect in interleukin-2 (IL-2) production. Reconstitution of the CARMA1-deficient cells with CARMA1 fully rescued this signaling defect. Together, our results show that CARMA1 is an essential signaling component that mediates TCR-induced NF-kappa B activation.