Over the last decade, it has been noted that nodular lymphocytic and/or histiocytic predominance Hodgkin's disease (NLPHD) has clinical, histological, and immunophenotypical differences from classical Hodgkin's disease, but it is not clear whether NLPHD represents a B-cell neoplasm or merely an unusual B-lineage reactive condition. We evaluated 36 cases of LPHD (31 nodular, 5 diffuse) for evidence of B-cell clonality by immunohistochemistry for light-chain protein using polyclonal antibodies and microwave antigen retrieval, and by a highly sensitive in situ hybridization technique for light-chain mRNA using 3H-labeled antisense RNA probes. We found monotypic light-chain restriction for kappa protein in 36% of cases, with no clear predominance for either light-chain protein in the other cases. By in situ hybridization, 80% of the evaluable cases showed clear evidence of light-chain monotypsim, with 96% of cases monotypic for kappa mRNA and one case monotypic for lambda mRNA. In virtually all of these cases, the L&H cells were found to be monotypic, consistent with monoclonality. In about one-half of these cases, a small lymphocytic component was also found to be monotypic. Our data support the hypothesis that NLPHD and its rare diffuse variant represent a monotypic B-cell neoplasm, almost always of kappa light-chain type. NLPHD represents a neoplasm distinct from classical Hodgkin's disease.