Human immunodeficiency virus (HIV) infection-associated B-cell hyperstimulation, in particular, the chronic stimulation of B cells to undergo isotype switching, may play an important role in the pathogenesis of acquired immunodeficiency syndrome-associated lymphoma (AIDS lymphoma). Isotype switching can be induced by various immune system factors, including cytokines, cell-surface stimulatory molecule interactions, and CD23. CD23 is a B-cell differentiation and activation marker expressed on mature B cells that is lost after isotype switching; soluble CD23 (sCD23) also is a B-cell-stimulatory factor. Because sCD23 is associated with Ig isotype switching, and because an enhancement of isotype switching may contribute to the genesis of AIDS lymphoma, we examined serum sCD23 levels in a retrospective study of HIV-seropositive subjects who had gone on to develop lymphomas. Subjects were participants in the Multicenter AIDS Cohort Study at UCLA, a study of the natural history of AIDS. Greatly elevated sCD23 serum levels were seen in subjects who developed AIDS lymphoma, when compared with others with AIDS (without lymphoma), or to HIV-seronegative or HIV-seropositive subjects who did not have AIDS. Because the induction of IgE has been tied to the activity of CD23, serum IgE levels were also examined in this study, and found to be significantly elevated in those who developed AIDS lymphoma. These findings suggests that serum sCD23 levels potentially may serve as a clinical tool for early detection of lymphomas in people who have HIV infection. Also, these observations provide clues on possible pathogenetic mechanisms that result in lymphomagenesis in the context of HIV infection and AIDS.