Even with routine immunohistochemical evaluation, distinguishing classic Hodgkin lymphoma (CHL) from diffuse large B-cell lymphoma (DLBCL) or anaplastic large cell lymphoma (ALCL) can be difficult. In these cases, the transcription factors (B cell-specific activator protein [BSAP], octamer-binding transcription factor 2 [Oct-2], and B-cell Oct-binding protein 1 [BOB.1]) and the pan-B-cell markers (CD20, CD22, and CD79a) may aid in clarifying the diagnosis. In 57 cases of CHL, 5 cases of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and 33 cases of non-Hodgkin lymphoma (25 DLBCL and 8 ALCL) we found the transcription factor phenotype BSAP+ and either Oct-2- or BOB.1- to be predictive of CHL; BSAP+/Oct-2+/BOB.1+ was predictive of NLPHL or DLBCL, while BSAP- was predictive of ALCL. Expression of all 3 pan-B-cell markers was seen only in NLPHL and DLBCL; positivity for a single B-cell marker was present only in CHL. Thus, together, the transcription factors and pan-B-cell markers might be useful in the differential diagnosis of CHL.