Lymphoid cancers are mainly classified according to their clinical presentation, morphology, immunology and molecular genetic features. Diagnosis of Hodgkin lymphoma (HL) is mainly based on pathognomonic Hodgkin and Reed-Sternberg cells (HRS). However, in the group of non-Hodgkin lymphomas (NHL), diffuse large B-cell lymphoma (DLBCL) can resemble typical features of HL. In some cases, a diagnostic pitfall exists at the interface of HL and DLBCL, so that, morphological overlaps and missing clear-cut diagnostic criteria complicate classification of these so-called gray zone lymphomas (GZL). In a recent study, we analyzed a newly established GZL cell line (SIP-F1) derived from a lymph node biopsy of a male 20-year-old lymphoma patient. Histological sections of the primary GZL were characterized by striking pleomorphism of in part multinuclear blast infiltrates and areas of necrosis. Immunohistochemistry revealed tumor cell positivity for the markers CD15, CD20 and CD30. SIP-F1 presented clonal Ig gene rearrangement and flow cytometry analysis showed expression of B-cell markers as well as 50-60% positivity for HL marker CD30. In addition, we observed tumor growth of SIP-F1 in a xenograft mouse model, morphologically resembling the primary tumor with lacunar HRS-like cells growing in sheets. For closer characterization, we performed gene expression profiling (GEP) and compared SIP-F1 to several B-cell lymphoma cell lines. The GEP of SIP-F1 did not cluster with any of the compared entities. Interestingly, but yet quite surprisingly, cytogenetic analysis revealed a normal karyotype. As SIP-F1 is positive for EBV, the cell line probably displays more a transformed B-cell clone than a GZL cell line. The patient, SIP-F1 is derived from, showed fast tumor rejection after initialization of chemotherapy. We were able to receive T cells for a co-culture study and could show that his immune system regained anti-tumor strength. In conclusion, considering the paucity in prospective differentiation of GZL cases, their distinct clinical behavior and treatment, we think that SIP-F1 could be a helpful tool to study morphological and molecular features of GZL and to better understand the biology of these unusual cases, although we are still tackling the question, what is the real tumor cell clone.