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To characterize the immune modulatory effects of 5-HT3 receptor antagonist treatment in patients with fibromyalgia, autoimmune disorders, and chronic pain.Multiplex-assisted cytokine measurements were performed before and during treatment. Whole blood stimulation with TNF-α was carried out to determine the proinflammatory response induced by exogenous TNF-α.Five of nine patients clinically responded to treatment, and two had a moderate response. All patients had significantly elevated levels of T-H1 cytokines more prominent than TNF-α, IL-1β, and IL-6. Treatment resulted in transient effects on peripheral monocyte counts in all but one patient, a plasma IL-1β increase in two responder patients, and decreased T-H1 cytokines in two responder patients. Ex vivo TNF-α stimulation was transiently reconstituted in three responder patients to a significant level. Three patients showed a marginal reconstitutive response.5-HT3 receptor blockade transiently affects monocyte tissue infiltration, modulates T-H1 cytokines in clinical responders as well as MIP-1β in moderate responders, and transiently affects the ex vivo response to exogenous TNF-α.