Significance Fibrosis is a leading cause of death in industrialized countries. Until now, there has been no effective therapy to prevent or counteract the fibrotic process. This article describes the effect of the blockade of a late costimulatory molecule to prevent inflammation-driven skin, lung, and vessel fibrosis and to induce regression of established dermal fibrosis in vivo in complementary murine models of systemic sclerosis, a prototypic autoimmune fibrotic disease. This article also reveals an unexpected role of this protein as a biomarker of worsening fibrosis that might help delineate the prognosis of patients in clinical practice more accurately.