Systemic Castleman's disease shows characteristic morphologic features in the lymph node and laboratory findings, but patients with this disease have variable clinical courses. The disease may constitute a spectrum of benign to malignant diseases. Thus, the clonal nature of the proliferating lymphoid cells was determined to obtain further insight into the malignant process of the disease. Two cases of systemic Castleman's disease were evaluated immunophenotypically, immunogenotypically, and cytogenetically. Both patients had a chronic relapsing clinical course. One patient had a clonal rearrangement of the immunoglobulin (Ig) lambda chain gene, but no restriction of the light chain expression was detected. This patient showed germ-line configurations of the Ig heavy-chain and T-cell receptor (TCR) beta chain genes; no detectable abnormal metaphases in the lymph node were noted. Another patient had predominance of lambda chain-positive plasma cells in the lymph node with a clonal chromosome change, but had germ-line Ig and TCR beta chain genes. The authors identified clonal changes in two cases of systemic Castleman's disease; one had a clonal immunogenotypic change and the other had a clonal cytogenetic change with an Ig light chain deviation. In both cases, however, a discordance of immunogenotypic and immunophenotypic changes was evident. Thus, the alteration may represent a type of lymphoproliferative disorder that lies between benign and malignant diseases.