Since the beginning of the AIDS epidemic, there has been considerable research on the etiology of Kaposi's sarcoma (KS) among HIV-infected individuals. A number of studies have confirmed that HIV or HIV-encoded products can interact with human cells to induce the production of cytokines, including interleukin 6 (IL-6). In vitro observations have indicated that AIDS-KS cells can produce significant levels of IL-6 and also respond to this cytokine. Preliminary data suggested that IL-6 may be elevated among HIV-infected individuals that subsequently develop AIDS-KS. The objective of this study was to determine if elevated levels of IL-6 are associated with an increased incidence of AIDS-KS compared to other AIDS-defining illnesses such as opportunistic infections (OIs). Serum IL-6 levels were determined by ELISA in frozen sera collected from participants in the Multicenter AIDS Cohort Study (MACS) at 6 months prior to AIDS diagnosis, in 73 cases (AIDS-KS), and 152 controls (OI). Elevated IL-6 levels were more prevalent among men with AIDS-OI than those with AIDS-KS: crude odds ratio (OR), 0.4 (95% CI, 0.2-0.9). Models of multivariate logistic regression were used to study potential confounders. Sexual behavior variables did not seem to confound the association between IL-6 and AIDS-KS. The higher prevalence of IL-6 among controls could be explained by the association of higher levels of IL-6 with lower levels of CD4 T cell number. IL-6 may be a marker of severe immune dysfunction among HIV-infected individuals.