BACKGROUND: Lymphedema is one of the serious clinical problems that can occur after surgical resection of malignant tumors such as breast cancer or intra-pelvic cancers. However, no effective treatment options exist at present. Here, we report that implantation of adipose-derived regenerative cells (ADRCs) can induce lymphangiogenesis in a mouse model of reparative lymphedema. METHODS AND RESULTS: ADRCs were isolated from C57BL/6J mice. To examine the therapeutic efficacy of ADRC implantation in vivo, we established a new mouse model of tail lymphedema. Lymphedema was improved significantly by local injection of ADRCs (P<0.05). Histological analysis revealed that lymphatic capillary density was greater in the ADRC group than in the phosphate-buffered saline control group (P<0.01). Tissue expression of vascular endothelial growth factor C mRNA and plasma levels of vascular endothelial growth factor C were greater in the ADRC group than in the control group (P<0.01 and P<0.05, respectively). ADRCs released vascular endothelial growth factor C, which directly stimulated lymphangiogenesis. Implantation of ADRCs also enhanced recruitment of bone marrow-derived M2 macrophages, which served as lymphatic endothelial progenitor cells. CONCLUSIONS: Implantation of autologous ADRCs could be a useful treatment option for patients with severe lymphedema via mediation of lymphangiogenesis. (J Am Heart Assoc. 2012;1:e000877 doi: 10.1161/JAHA.112.000877.).