Introduction: Free flap lower extremity repair is associated with a high complication rate ( > 31%); higher rates are observed in more severe patients. In cases requiring prior systemic/local stabilization, delayed repair increases complication rate (+10% at 7 days): Negative-pressure Wound Therapy (NPWT) decreases complications but only when applied for less than 7 days. Recent limited evidence suggests that augmentation of NPWT with instillation for wound irrigation (NPWTi) might safely extend such window. This study hypothesizes that, through the combined cleansing effect of NPWT and instillation, NPWTi allows safe (low complication rate) delayed free flap repair in severe patients with Gustilo IIIb injuries (GIIIb). Methods: A prospective case series was designed (inclusion criteria: GIIIb requiring microsurgical repair, severe patient/injury condition preventing immediate/early repair; exclusion criteria: allergy to NPWTi dressing). Patients received NPWTi (suction: 125 mmHg continuous; irrigation: NaCl 0.9%) until considered clinically ready for repair. Preoperative/postoperative complications (dehiscence, wound infection, bone non-union, osteomyelitis, flap failure) were monitored with clinical signs, imaging, and serum markers (CRP, WBC). Results: Four patients (male: N = 4, female N = 1; Age: 59 [44-75] years-old) were treated. NPWTi was applied for 15.2 [9-28] days. No complication (0%) was observed preoperatively or postoperatively. Delayed repair occurred by latissimus dorsi musculocutaneous flap (N = 3), and anterolateral thigh flap (N = 2). All patients walked weight-bearing 12 [6-20] weeks after injury. Conclusions: NPWTi seems to allow safe delayed free flap repair in patients with severe lower extremity injuries unable to undergo immediate/early repair.