Hodgkin's and Reed-Sternberg (H-RS) cells are morphological hallmarks of Hodgkin's disease (HD). So far, several characteristics frequently seen in H-RS cells from different origins have been described, such as the high expression of Epstein-Barr virus latent membrane protein 1 (LMP1), the elevation of NF-kappaB activity, and the aberrant expression of molecules such as CD15, CD30, and CD99. Despite extensive studies on the nature of H-RS cells, the molecular mechanism by which H-RS cells are generated remained elusive. Recently, the forced down-regulation of CD99 was reported to induce typical H-RS phenotypes in vitro in a B cell line. Furthermore, it was revealed that LMP1 markedly reduces the CD99 expression at the transcriptional level. Since the presence of LMP1 is known to be associated with the H-RS cell formation, the data provide a possibility of linkage between LMP1 and HD via CD99, thus suggesting that, at least in part, the loss of CD99 may play a critical role in the pathogenic sequence to the formation of H-RS cells in HD. In this review, the role of CD99 in the generation of H-RS cells and its molecular mechanism will be suggested.