Introduction: Meshed split-thickness skin grafting represents a rapid and effective technique for surgical wound closure. Factors such as ongoing inflammation, microbial colonization, and a poorly vascularized wound bed increase the rate of skin autograft failure up to 33%. Because of the inherent angiogenic, anti-inflammatory, antimicrobial, and antifibrotic properties of human placental membranes, the complementary use of human placental membranes may promote graft survival and improve success rate for complete ulcer resolution. Methods: In this case series, a viable cryopreserved placental membrane was used as a meshed split-thickness skin grafting overlay in 6 high-risk patients with various comorbidities and recalcitrant nonhealing lower-extremity wounds. Results: The mean size of grafted wounds was 130.3 cm2. The average graft take-rate by postoperative days 10 to 14 was 92.5%, with complete epithelialization of all skin graft interstices observed between days 10 and 21. Transplanted autograft tissues did not lyse or dissolve, and sites remained free of infection and maceration throughout postoperative follow-up. Complete wound closures remained intact at the 12-month follow-up visit. Discussion: Thus far, our clinical experience has warranted the complementary use of viable cryopreserved placental membrane and meshed split-thickness skin grafting to reduce the need for repeat surgical interventions or prolonged local wound care due to graft loss or failure in high-risk patients.