CD30 is a lymphoid cell-specific surface receptor which was originally identified as an antigen expressed on Hodgkin’s lymphoma cells. Activation of CD30 induces the nuclear factor κB (NF-κB) transcription factor. In this study, we define the domains in CD30 which are required for NF-κB activation. Two separate elements of the cytoplasmic domain which were capable of inducing NF-κB independently of one another were identified. The first domain (domain 1) mapped to a ~120-amino-acid sequence in the membrane-proximal region of the CD30 cytoplasmic tail, between residues 410 and 531. A second, more carboxy-terminal region (domain 2) was identified between residues 553 and 595. Domain 2 contains two 5- to 10-amino-acid elements which can mediate the binding of CD30 to members of the tumor necrosis factor receptor-associated factor (TRAF) family of signal transducing proteins. Coexpression of CD30 with TRAF1 or TRAF2 but not TRAF3 augmented NF-κB activation through domain 2 but not domain 1. NF-κB induction through domain 2 was inhibited by coexpression of either full-length TRAF3 or dominant negative forms of TRAF1 or TRAF2. In contrast, NF-κB induction by domain 1 was not affected by alterations in TRAF protein levels. Together, these data support a model in which CD30 can induce NF-κB by both TRAF-dependent and -independent mechanisms. TRAF-dependent induction of NF-κB appears to be regulated by the relative levels of individual TRAF proteins in the cell.