Aim: The goal of this study was to compare success rates of a regenerative limb salvage approach (rLS) using dehydrated human chorion amnion membrane (dHACM) to traditional flap-based limb salvage (fLS). Materials & methods: This prospective RTC enrolled patients presenting with complex extremity wounds over a 3-year period. Primary outcomes included success of primary reconstruction, persistence of exposed structures, time to definitive closure, and time to weight bearing. Results: Patients meeting inclusion criteria were randomized to fLS (n = 14) or rLS (n = 25). The primary reconstructive method was successful for 85.7% of fLS subjects and 80% of rLS subjects (p = 1.00). Conclusion: This trial provides strong evidence that rLS is an effective option in the setting of complex extremity wounds, with success rates comparable to traditional flaps. Clinical Trial Registration: NCT03521258 ( ClinicalTrials.gov )