Nodular lymphocyte predominant (NLP) Hodgkin's disease (NLP HD) has been recently suggested to be of B-cell derivation on the basis of phenotypic and morphologic findings. Consistent with this view, there are sporadic case reports of coexisting NLP HD and large cell lymphoma (LCL). We describe a compilation of seven unique cases of NLP HD selected from the NIH case consultation files in which lymphohistiocytic mononuclear variant cells (L&H) became clustered into increasingly large aggregates. In areas of the same tumor mass, large confluent sheets of these cells resembled LCL. In contrast to what would be expected for LCL, all patients had localized disease clinically, and six of seven achieved long-term disease-free survival following radiation therapy or chemotherapy (two cases) for HD. None of the patients developed disseminated LCL. Also notable was a high frequency of axillary lymph node involvement (five of seven) and the high rate of occurrence in blacks (six of seven). Immunophenotypic (in two cases) and molecular genetic analysis (in one case) was suggestive of B-cell derivation for the proliferating cells. These findings also raise the possibility that some so-called large cell lymphomas may actually represent histologically progressed NLP HD, and that such cases might be associated with a favorable prognosis comparable to that seen in NLP HD.