Introduction. Treatment modalities that overcome stalled wound healing in lower extremity wounds are crucial for reducing lower limb amputations, which have a 5-year mortality rate of an astounding 70%. Recent non-comparative studies have shown negative pressure wound therapy with instillation and dwell time (NPWTi-d) using a dressing comprised of reticulated open cell foam with through holes (ROCF-CC) provides favorable clinical outcomes for various wound types, including complex lower extremity wounds. Objective. The objective of this study is to compare NPWTi-d using ROCF-CC dressings (treatment group) with advanced wound dressings (control group) in patients with chronic lower extremity wounds and known systemic risk factors for delayed healing. Materials and Methods. A retrospective assessment was performed for 10 patients with complex lower extremity wounds that underwent an initial debridement and then were treated with either advanced wound dressings (control group; n = 5) or NPWTi-d using ROCF-CC dressings (treatment group; n = 5). Advanced wound dressings were applied to wounds and changed 1 to 3 times per week. Negative pressure wound therapy with instillation and dwell time was applied by instilling normal saline onto wounds, with a dwell time of 20 minutes, followed by continuous negative pressure (-125 mm Hg) for 2 hours. The ROCF-CC dressings were changed every 2 to 3 days. Results. Patients in the treatment group had significantly fewer wound complications (P = .024) and underwent significantly fewer surgical debridements (P = .004) when compared with patients in the control group. All wounds in the treatment group healed without complication, whereas only 2 of the 5 wounds in the control group healed. Demographics and comorbidities were similar between groups. Conclusions. These data further support the use of NPWTi-d with ROCF-CC to help manage complex wounds of the lower limb.