Functioning as a B-cell growth and differentiation factor, interleukin-6 (IL-6) may play an important role in the pathophysiology of B-cell tumors. The capacity for IL-6 secretion was evaluated in 58 patients with various B-cell leukemias/lymphomas and in four patients with Castleman's disease (CMD). Cell populations from various sites including peripheral blood, bone marrow, lymph nodes, and osteolytic bone lesions were cultured and tested for spontaneous or IL-1Β/ TNFα-induced IL-6 production in a sensitive bioassay. No significant IL-6 levels were released by the tumor cells in any of the B-cell leukemias or lymphomas tested, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL). In contrast, purified malignant plasma cells were found to secrete IL-6, strengthening the idea that an autocrine pathway for growth regulation in multiple myeloma (MM) exists. For the first time, in several patients with CMD, peripheral blood cells were shown to produce extremely high levels of IL-6, the pathogenetic significance of which remains to be elucidated. However, similar observations were very occasionally made in MM patients. Therapy with corticosteroids strongly inhibited this IL-6 production. These data provide evidence for autocrine and possibly an additional paracrine regulatory loop in plasma cell neoplasias and CMD.