The global loss of B-cell-specific gene expression is a distinctive feature of the Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin's lymphoma (HL). The reasons for this loss remained largely unknown as transcription factors with pleiotropic effects on B-cell-specific gene expression, namely E2A, EBF, and PAX5, are present in primary HRS cells. We show here that ID2, which can inactivate E2A and perhaps PAX5, is not detectable in normal B cells but is strongly and uniformly expressed in HRS cells of all cases of classical HL. Recurrent chromosomal gains of the ID2 gene might contribute to this aberrant expression. Co-immunoprecipitation of E2A with ID2 from HRS-derived cell lines together with the high amount of ID2 relative to the B-cell transcription factors E2A and PAX5 in HRS-derived cell lines and primary HRS cells indicated that aberrant ID2 expression contributes significantly to the loss of the B-cell-specific gene expression in HRS cells. ID2 was also expressed in lymphocyte-predominance HL, mediastinal large B-cell, diffuse large B-cell, and Burkitt's lymphoma, where lower amounts of ID2 relative to E2A and PAX5 compared with HRS cells might prevent a global down-regulation of B-cell-specific genes and ID2 may contribute to lymphomagenesis in other ways.