Highest mediastinal lymph node (HMLN) involvement is a category of uncertain resection, yet the prognostic significance of HMLN involvement remains controversial.A total of 486 patients with pathological stage III-N2 disease who underwent radical resection were enrolled from January 2015 to December 2018. Patients were allocated into two groups-HMLN involvement (219 cases) and HMLN-negative (249 cases) groups. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of HMLN involvement on 5-year recurrence-free survival (RFS) and overall survival (OS).The proportion of patients with multiple N2 diseases (72.1% vs. 23.7%; p < 0.001) and stage IIIA (87.2% vs. 77.5%; p < 0.009) were greater in the HMLN-involvement group than in the HMLN-negative group, and the survival rates of the HMLN-involvement group were significantly lower than those of the HMLN-negative group (RFS: 27.2% vs. 49.8%, p < 0.001; OS: 42.1% vs. 59.2%, p = 0.001). HMLN status was an independent factor for OS only (RFS: adjusted hazard ratio [aHR] 1.26, 95% confidence interval CI 0.94-1.68; OS: aHR 1.45, 95% CI 1.07-1.99) in the entire stage III cohort. After stratification of patients according to stage, the involvement of HMLN decreased both RFS and OS in the stage IIIA group (RFS: aHR 1.46, 95% CI 1.06-2.02; OS: aHR 1.70, 95% CI 1.19-2.42); however, no such difference was observed within the stage IIIB group.HMLN involvement is a prognostic factor of deteriorating survival in highly advanced N2 disease only in patients with stage IIIA.© 2024. Society of Surgical Oncology.