Using Zucker fatty rats, a strain characterized by diabetes, and hyperlipidemia, we investigated the diabetes- and hyperlipidemia-related impairment of bone marrow mononuclear cells (BM-MNCs) for inducing therapeutic angiogenesis. BM-MNCs from Zucker fatty and normal Zucker lean rats were collected and cultured. Although the characterization and cell survival of BM-MNCs did not differ, the VEGF production, endothelial differentiation, and endothelial cell colony-forming potential of BM-MNCs from Zucker fatty rats were significantly lower than those of BM-MNCs from lean rats. Using an ischemic hindlimb model, we found that the native recovery of induced limb ischemia in the Zucker fatty rats was also significantly worse than that in the lean rats. Furthermore, the expression of 5-hydroxytryptamine (5-HT_2A) receptors was obviously higher in the Zucker fatty rats than that in the lean rats, and enhanced after limb ischemia. Although the therapeutic potency was lower than the implantation of BM-MNCs from normal lean rats the implantation of BM-MNCs from fatty rats could also induce angiogenesis and increase blood flow significantly in the ischemic hindlimbs of Zucker fatty rats. Furthermore, the blood flow in the ischemic hindlimbs was increased by the administration of sarpogrelate, a selective 5-HT_2A receptors antagonist. Our results clearly show diabetes- and hyperlipidemia-related dysfunction and impaired potency for inducing angiogenesis of BM-MNCs. However, the implantation of autologous BM-MNCs into ischemic limb of diabetic and hyperlipidemia rats has induced therapeutic angiogenesis effectively, and blood flow would be enhanced by the administration of a 5-HT_2A receptor antagonist.