Hodgkin's lymphoma (HL) is separated into the classical (c) and lymphocyte-predominance (lp) forms. Whereas classical Hodgkin-Reed/Sternberg (HRS) cells carry mutated immunoglobulin (Ig) gene rearrangements that are often "crippled" and lack intraclonal diversity, and are likely derived from preapoptotic germinal center (GC) B cells, the lymphocytic and histiocytic cells of lpHL are presumably derived from selected GC B cells and often show ongoing somatic hypermutation. The recently identified lymphocyte-rich classical (lrc) HL is characterized by HRS cells with the immunophenotype of classical HRS cells (CD30(+)CD15(+)CD20(-)CD45(-)) but an infiltrate similar to lpHL and a clinical behavior resembling lpHL. To identify the histogenetic origin of the HRS cells in lrcHL and to determine the relationship to the lymphoma cells of cHL and lpHL we characterized seven cases of lrcHL by immunohistochemistry and sequenced the rearranged Ig genes of single micromanipulated HRS cells. The expression patterns of BCL6, CD138, Oct2, and BOB1 in HRS cells of lrcHL showed differences to those of both cHL and lpHL. Analyses of rearranged Ig genes identified clonal HRS cell expansions carrying mutated Ig rearrangements without significant intraclonal diversity in all seven of the cases. In two cases crippling mutations, rendering originally functional V gene rearrangements nonfunctional, were observed. Thus, the mutation pattern of rearranged Ig genes of HRS cells in lrcHL is clearly different from those in lymphocytic and histiocytic cells of lpHL, and resembles the pattern in HRS cells of cHL, suggesting that HRS cells in lrcHL derive from (preapoptotic) GC B cells that silenced hypermutation. In one case in addition to the dominant HRS cell clone, CD30(+) EBV-infected HRS-like cells unrelated to the tumor clone were observed, suggesting development of an expanded population of EBV-harboring HRS-like cells in the microenvironment of HL.