This multicenter, retrospective study presents the use of a human acellular dermal regenerative tissue matrix as an alternative treatment for 100 chronic, full-thickness wounds of the lower extremity in 75 diabetic patients. Comorbidities included cardiac disease (86.0%), neuropathy (86.0%), peripheral vascular disease (82.0%), infection (54.0%), obesity (51.0%), and osteomyelitis (37.0%). Wound locations included the foot (86.0%), ankle (8.0%), and lower extremity (6.0%). Mean wound age was 20.4 weeks (1.3-191.4 weeks). University of Texas (UT) wound classifications included 15 (15.0%) 1A, 1 (1.0%) 1B, 1 (1.0%) 1C, 2 (2.0%) 1D, 18 (18.0%) 2A, 8 (8.0%) 2B, 5 (5.0%) 2C, 3 (3.0%) 2D, 3 (3.0%) 3A, 7 (7.0%) 3B, 3 (3.0%) 3C, and 34 (34.0%) 3D. The mean time to matrix incorporation, 100% granulation, and complete healing was 1.5 weeks (0.43-4.4 weeks), 5.1 weeks (0.43-16.7 weeks), and 13.8 weeks (1.7-57.8 weeks), respectively. The overall matrix success rate, as defined by full epithelialization, was 90.0%. One failed wound subsequently healed approximately 7 weeks after matrix reapplication. The healing rate was 91.0%, as 91 of the 100 wounds healed. No statistically significant differences were observed between UT classifications and time to matrix incorporation, 100% granulation, and complete healing. Absence of matrix-related complications and high rates of closure in a wide array of diabetic wounds suggest that this matrix is a viable treatment for complex lower extremity wounds. Lack of any statistically significant differences between UT grades and wound outcome end points lends further support to the universal applicability of this matrix, with successful results in both superficial diabetic wounds and in wounds penetrating to the bone or joint.