Postmastectomy breast reconstruction remains one of the most frequently performed plastic surgery procedures in the United States. Acellular dermal matrix has been used extensively in expander-implant breast reconstruction and therefore is an appropriate material to be used to develop a clinically relevant animal model of breast reconstruction. The study population consisted of 18 female Yorkshire pigs, which were assigned randomly to bilateral expander breast reconstruction with either AlloMax Surgical Graft or AlloDerm Regenerative Tissue Matrix (n = 9 per group). Each group was further randomized to 4-, 8-, or 12-week time points (n = 3), to evaluate integration and neovascularization by means of microcirculatory and histologic techniques. Microcirculatory analysis revealed early acellular dermal matrix angiogenesis at 4 weeks on the skin flap surfaces only, and well-formed vasculature on both acellular dermal matrix surfaces at 8 weeks. Both surfaces were vascularized and exhibited detectable flow at 12 weeks after implantation. Progressive acellular dermal matrix angiogenesis was also histologically observed over time by means of hematoxylin and eosin-stained slides, as indicated by direct vascular identification/scoring at 4, 8, and 12 weeks. The authors have developed a clinically relevant large-animal model of breast reconstruction using acellular dermal matrix. The acellular dermal matrix inflammatory, neovascularization, and tissue integration response should be evaluated in an in vivo setting that accurately simulates the anatomy, biomaterials, surgical techniques, and timeframes encountered in human postmastectomy breast reconstruction to appropriately predict clinical performance. Neovascularization of the acellular dermal matrix with detectable blood flow took place after postimplantation week 8, a much slower process than previously reported in models not clinically relevant to acellular dermal matrix-assisted tissue expander breast reconstruction.