CD30 is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on activated lymphocytes, as well as on neoplastic cells of Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). A number of reports have shown that, depending on cellular context, CD30 signaling can exert a variety of effects, ranging from cell death to cellular proliferation. In the present study this disparity was examined, using a number of ALCL- and HD-derived cell lines. Activation of CD30 led to the induction of apoptotic death of ALCL cells, along with the selective reduction of TNF receptor-associated factor 2 and impairment in the ability of these cells to activate the pro-survival transcription factor nuclear factor kappa B (NF-kappa B). In contrast, HD cells, which constitutively express NF-kappa B, were not susceptible to CD30-induced apoptosis but could be sensitized following ectopic overexpression of a superdominant I kappa B. These studies suggest that NF-kappa B plays a determining role in the sensitivity or resistance of lymphoma cells to CD30-induced apoptosis, which may have important consequences in the clinical treatment of CD30-positive neoplasia. (Blood. 2000;96:4307-4312)