Background Technology to assess tissue perfusion is exciting with translational potential, although data supporting its clinical applications have been lagging. Patients who have undergone radiation are at particular risk of poor tissue perfusion and would benefit from this expanding technology. We designed a prospective clinical trial using intraoperative indocyanine green angiography to evaluate for wound-healing complications in patients undergoing salvage laryngectomy after radiation failure. Patients and Methods This prospective trial included patients undergoing salvage laryngectomy at a National Cancer Institute-designated tertiary cancer center between 2016 and 2018. After tumor extirpation and prior to reconstruction, 10 mg indocyanine green dye was infused and the fluorescence ( F HYPO ) and ingress rate of the pharyngeal mucosa recorded. The primary outcome measure was formation of a pharyngocutaneous fistula (PCF). Results Patients who developed a PCF had significantly lower F HYPO (87 vs 172, p  < 0.001) and ingress rates (6.7 vs 15.8, p  = 0.043) compared with those who did not develop a fistula. There were no fistulas in patients with F HYPO  > 150 ( n  = 21) or ingress > 15 ( n  = 15). There was a 50% fistula rate in patients with F HYPO  ≤ 103 ( n  = 10) and ingress rate ≤ 6 ( n  = 6). Conclusions Intraoperative indocyanine green angiography can assess hypoperfusion in patients and predict risk of PCFs after salvage laryngectomy, and can thus intraoperatively risk-stratify patients for postoperative wound-healing complications.