Chronic fatigue syndrome (CFS) is an idiopathic illness associated with a variety of immunologic abnormalities. To investigate potential pathogenetic mechanisms, we evaluated serum levels and peripheral blood mononuclear cell (PBMC) production of selected cytokines and immunoglobulins. Serum bioactive transforming growth factor beta (TGF-β) levels were high (P < 0.01) in patients with CFS (290 ± 46 pg/mL) than in control subjects (104 ± 18 pg/mL), but levels of other cytokines tested were not different. Lipopolysaccharide-stimulated release of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-alpha was increased (P < 0.05) in PBMC cultures from patients with CFS versus control subjects; enhanced (P < 0.01) IL-6 release to phytohemagglutinin was also observed. In contrast, TGF-β release in response to lipopolysaccharide was depressed (P < 0.01) in PBMC cultures derived from patients with CFS. No differences in IL-2 and IL-4 or immunoglobulin production were observed. The enhanced release of inflammatory cytokines by stimulated PBMC from patients with CFS suggests that these cells are primed for an increased response to immune stimuli. These data also suggest an association between abnormal regulation of TGF-β production in vivo and in vitro with the immunologic consequence of CFS.