Abstract Background To evaluate the efficacy of the surgical fat-filling procedure (SFFP) in the treatment of refractory cough and quality of life (QOL) after systematic mediastinal lymphadenectomy in patients with right lung cancer. Methods This is a blinded, randomized, controlled clinical trial to evaluate refractory cough and QOL in patients after mediastinal lymphadenectomy for lung cancer. One hundred eligible lung cancer patients were randomly divided into two groups: the fat-filling group and non-filling group. In the fat-filling group, post-lymphadenectomy residual cavities (PLRCs) were filled with fatty tissue autografts after lymph node dissection. In the non-filling group, the PLRCs remained unfilled. Clinical endpoints were postoperative cough score and QOL. Results The SFFP did not increase intraoperative bleeding, extend operation time, or hospital stay. Further, night cough was significantly improved after 4 wk in the fat-filling group after the removal of a chest drainage tube. QOL issues, such as emotional condition, functional status, and additional concerns, demonstrated a remarkable improvement in the fat-filling group at postoperative 1 mo compared with the non-filling (control) group. Conclusions This study demonstrates that filling PLRCs with fatty tissue autografts is a safe and partially effective treatment for refractory cough after major pulmonary resection and mediastinal lymphadenectomy. This novel procedure significantly improved patient QOL and may prove useful as a relatively safe preventive surgical adjunct operation for refractory cough.