Reed-Sternberg (RS) cells represent a histopathologic hallmark for Hodgkin lymphoma (HL). Viral proteins may induce aberrant expression of cyclin A and lead to multinucleation in virus-infected cells. We investigated whether Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) and cyclin A are involved in the morphogenesis of RS cells. We immunohistochemically analyzed "individual" tumor cells in 34 HLs for the subcellular expression of cyclin A and HL-related markers. In LMP1+ and LMP1- HLs, multinucleated RS cells aberrantly expressed cyclin A in cytoplasm, while the mononuclear Hodgkin cells expressed cyclin A predominantly in nuclei (P < .001). No differential expression of CD15, CD30, or CD99 in HL cells was found. In vitro, EBV-LMP1 increased cytoplasmic cyclin A expression and multinucleation in an HL cell line. Therefore, the aberrant expression of cyclin A is commonly associated with RS cell morphologic features in HL, probably through LMP1 signaling or other similar mechanisms in EBV- cases.