Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are both secreted by in vivo-activated normal B cells and by in vivo-activated B cells from patients with polyclonal B-cell activation, including individuals infected with the human immunodeficiency virus (HIV). Furthermore, IL-6 and TNF-alpha are involved in autocrine and paracrine regulation of human B-cell differentiation. Following in vitro stimulation of normal B cells with Staphylococcus aureus Cowan strain I and IL-2, there is a rapid but brief increase in supernatant levels of TNF-alpha. There is also an initial increase followed by a subsequent and more sustained increase in IL-6 production. The secondary rise in IL-6 production is dependent upon the prior production of TNF-alpha. There is no significant difference in IL-6 and TNF-alpha secretion by CD5 positive versus CD5 negative tonsillar B cells. Ig production by normal in vitro-activated B cells and freshly isolated B cells from patients with hypergammaglobulinemia is largely dependent upon TNF-alpha and IL-6 production. As another measure of B-cell TNF-alpha and IL-6 production, freshly isolated B cells from HIV-infected individuals induce virus production by chronically HIV-infected cells in which HIV production is known to be triggered by a variety of cytokines. By contrast, freshly isolated B cells from normal controls fail to increase HIV production unless they are stimulated in vitro. Thus, the spontaneous production of IL-6 and TNF-alpha by B cells from individuals infected with HIV may contribute to viral expression as well as to the hypergammaglobulinemia often associated with HIV infection.