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Patients with head and neck or esophageal cancer who undergo resection and reconstructive surgery sometimes develop fistulae that exhibit delayed wound healing. We developed a novel negative pressure wound therapy (NPWT) that employs a Penrose drain. This case series report describes its effect on the wound healing and treatment duration of cancer patients with postoperative fistulae.This consecutive case series consisted of all patients from February 2014 to February 2017 who underwent resection and reconstruction for head and neck or esophageal cancer and who then developed a fistula that was treated with either NPWT or a second flap that did not resolve the fistula or led to fistula recurrence and was then treated with NPWT. A Penrose drainage tube was inserted into the fistula, and a NPWT device was applied.Eleven patients (10 males, 1 female; mean age, 67.4 years) underwent NPWT for fistulae that arose after tumor resection and reconstruction (n = 6) or after fistula reconstruction (n = 5). The resection was for esophageal (n = 4), laryngeal (n = 3), oral (n = 2), and hypopharyngeal (n = 2) cancer. In 9 cases, 1 week of NPWT led to rapid and complete wound healing. In 2 cases, complete healing occurred after 3–4 weeks of NPWT.Our NPWT applies continuous negative pressure inside the fistula only and dramatically promoted fistula healing. This approach may work by cleaning the fistula and promoting mucosal surface adhesion. It is particularly effective when the tissue surrounding the fistula is soft due to fresh tissue transfer.