The NF-κB/Rel family of transcription factors regulates a wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-κB/Rel proteins and their IκB regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-κB/Rel/IκB signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed–Sternberg (H/RS) cells in a reactive background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin and Reed–Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-κB transcription factor. Here, we report the detection of mutations of the IkBa gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective IκBα is thus likely to explain the constitutive activation of NF-κB in these cells and suggests that IκBα is a tumour suppressor controlling the oncogenic activation of NF-κB in Hodgkin and Reed–Sternberg cells.