Background and Purpose Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5‐HT system is associated with VHD. Here, we investigated the contribution of 5‐HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex. Experimental Approach Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr2B ‐/‐, Htr2A ‐/‐, and Htr2B/2A ‐/‐) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT –qPCR. Samples of human prolapsed mitral valves were also analysed. Key Results Chronic treatment of mice with nordexfenfluramine activated 5‐HT2B receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5‐HT2A or 5‐HT2B receptor antagonists and in transgenic Htr2B −/− or Htr2A/2B −/− mice. Surprisingly, valve lesions were mainly formed by numerous non‐proliferative CD34+ endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM‐derived CD34+CD31+ cells by 5‐HT2B receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non‐proliferating CD34+/CD309+/NOS3+ endothelial progenitors expressing 5‐HT2B receptors. Conclusions and Implications BM‐derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.