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Several lines of research indicate that serotonin (5-hydroxytryptamine, 5-HT) and 5-HT receptors may play a part in the pathogenesis of chronic inflammatory rheumatic conditions like rheumatoid arthritis (RA) and scleroderma/progressive systemic sclerosis (PSS). In this paper, case reports on two patients with RA who were successfully treated with 5-HT3 receptor antagonist tropisetron were presented. Short-term oral tropisetron (5–10 mg/d) induced either remission of RA or improvement in RA-related symptoms, which lasted for several weeks or months after the treatment was discontinued. Interestingly, tropisetron was effective in a patient with refractory rheumatoid vasculitis, which is a severe complication that requires high-dose glucocorticoids in most cases. The beneficial effect of 5-HT3 receptor antagonists in RA and PSS suggests that this class of drugs may have potential in the treatment of chronic inflammatory rheumatic conditions. Double blind, placebo-controlled studies are urgently needed to confirm the efficacy and tolerance of 5-HT3 receptor antagonists in larger cohorts of patients.