OBJECTIVES: Systemic sclerosis (SSc) is a connective tissue disease with fibrotic remodeling of the skin and various internal organs. SSc is associated with the highest case-specific mortality of all rheumatic autoimmune diseases with limited antifibrotic treatment options. Here, we evaluated the therapeutic effects of the highly selective 5-hydroxytryptamine 2B receptor (5-HT METHODS: The antifibrotic effects of AM1476 were evaluated in the mouse models of bleomycin-induced pulmonary fibrosis, in tight-skin-1 (Tsk-1) mice and in mice with sclerodermatous chronic graft-versus-host disease (cGvHD). For further validation, the antifibrotic effects of AM1476 were analyzed in precision cut skin (PCS) slices from SSc patients. RESULTS: AM1476 demonstrated high selectivity for 5-HT CONCLUSIONS: We describe AM1476 as a highly selective inhibitor of 5-HT