Background: Despite promising pre-clinical results, transient single-factor based therapeutic angiogenesis has shown no definitive benefits in clinical trials. The use of skin-derived micro-organs (SMOs), capable of sustained expression of angiogenic factors and sustained viability with their cellular and extracellular elements, constitutes an attractive alternative. We sought to evaluate the efficacy of SMO implantation in a porcine model of chronic myocardial ischemia. Methods and Results: Eighteen pigs underwent placement of an ameroid constrictor on the proximal circumflex artery. Three weeks later, split-thickness skin biopsies were harvested and pigs were randomized to lateral wall implantation of either 8 or 16 SMOs, or blank injections. The procedure was safe and resulted in no adverse events. Three weeks after treatment, SMO implantation resulted in significant improvement of lateral wall perfusion during pacing, assessed by isotope-labeled microspheres (post- vs. pre-treatment ratios of lateral/anterior wall blood flow were 1.31±0.09 (SMOs) and 1.04±0.06 (controls), p= 0.03). No significant difference in angiographic scores were observed. Microvascular relaxation in response to VEGF was impaired in the ischemic territory of the control group, but returned to normal after SMO implantation indicating restoration of endothelial function. Molecular studies showed significant increases in VEGF and CD31 expression, respectively, in the ischemic area of treated animals. Morphometric analysis showed increased neovascularization with SMO treatment. Conclusions: Auto-transplantation of SMOs constitutes a novel approach for safe and effective therapeutic angiogenesis with improvement in perfusion, normalization of microvascular reactivity, and increased expression of VEGF and CD-31.