Classical Hodgkin lymphoma (HL) is a malignant disorder characterized by the presence of neoplastic mononucleated Hodgkin and multinucleated Reed-Sternberg cells. Here, we show that both the interleukin (IL)-21 receptor as well as IL-21 are expressed by HL cells. IL-21 activates signal transducer of activation and transcription 3 (STAT3) and STAT5 in HL cell lines and activated human B cells. Ectopic expression of constitutively active STAT5 in primary human B cells resulted in immortalized B cells that have lost the B-cell phenotype and strongly resembled HL cells, which could partially be rescued by ectopic expression of the B cell-determining transcription factor E47. Data from experiments using reporter assays and overexpression of constitutively active IKK2 support the hypothesis that the STAT5 and nuclear factor-kappaB (NF-kappaB) pathways collaborate in HL genesis.