Recent evidence suggests that nodular lymphocyte predominance Hodgkin's disease (NLPHD) is a distinct entity that may be related to progressively transformed germinal centers, abnormal B-lymphoid hyperplasia, and low-grade B-cell lymphoma. bcl-2 is a marker for the translocation t(14;18)(q32;q21), which occurs in most follicular-derived B-cell lymphomas. Eleven cases of NLPHD and 19 cases of Hodgkin's disease of nodular sclerosis (NSHD) and mixed cellularity (MCHD) type were analyzed for immunoglobulin JH gene rearrangement. bcl-2 translocation was determined with Southern blot analysis and the polymerase chain reaction using biotin labeled probes to the major breakpoint region and the alkaline phosphatase reaction. All cases of NLPHD were negative for JH gene rearrangement and bcl-2 translocation. Cases of NSHD and MCHD were similarly negative for bcl-2, although three cases exhibited clonal JH gene rearrangements. These results confirm that a clonal B-cell population is not detected in NLPHD. Cases of NLPHD differ from most low-grade follicular B-cell lymphomas in that they lack bcl-2 gene rearrangement and t(14;18) translocation at the major breakpoint region.