Large cell lymphoma (LCL) sometimes occurs concurrently or subsequently in patients with nodular lymphocyte-predominant Hodgkin disease (NLPHD). Although there is evidence of a clonal relationship between LCL and NLPHD, there has been no direct demonstration that the lymphocytic and histiocytic (L&H) cells in NLPHD are related to the tumor cells in LCL. We identified 2 cases of NLPHD with an associated LCL. Single L&H cells, the Reed-Sternberg cell variants in NLPHD, were isolated from immunostained tissue sections by micromanipulation, and the immunoglobulin heavy chain gene (IgH) complementarity determining region (CDR) III of the cells was amplified by the polymerase chain reaction (PCR). The products were compared with those obtained from microdissected LCL cells using polyacrylamide gel electrophoresis and nucleotide sequencing. The IgH CDRIII sequences from the L&H cells were related to each other, but also showed nucleotide substitutions, consistent with a germinal center origin. The sequences from the L&H cells also were related to those from the corresponding LCL cells. We have provided direct evidence through sequence analysis of the IgH CDRIII that the L&H cells are clonally related to the corresponding LCL arising in 2 cases of NLPHD.