Background: Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete resection is obtained. Factors associated with positive margins in this population are not well-studied., Methods: We performed a retrospective cohort study using National Cancer Database (NCDB) for adult patients with >5 cm, clinically node-negative NSCLC with evidence of invasion of nearby structures [2006-2015]. Patients were classified as having major structure involvement (azygous vein, pulmonary artery/vein, vena cava, carina/trachea, esophagus, recurrent laryngeal/vagus nerve, heart, aorta, vertebrae) or chest wall invasion (rib pleura, chest wall, diaphragm). Our primary outcome was to evaluate factors associated with incomplete resection (microscopic: R1, macroscopic: R2). Kaplan-Meier analysis and cox multivariable regression models were used to evaluate overall survival (OS), 90-day mortality, and factors associated with positive margins., Results: Among 2,368 patients identified, the median follow-up was 33.8 months [interquartile range (IQR), 12.6-66.5 months]. Most patients were white (86.9%) with squamous cell histology (47.3%). Major structures were involved in 26.4% of patients and chest wall invasion was seen in 73.6%. Four hundred and seventy-eight patients (20.2%) had an incomplete resection. Multivariable analysis revealed that black race [hazard ratio (HR) 1.568, 95% confidence interval (CI): 1.109-2.218] and major structure involvement (HR 1.412, 95% CI: 1.091-1.827) was associated with increased risk of incomplete resection and surgery at an academic hospitals (HR 0.773, 95% CI: 0.607-0.984), adenocarcinoma histology (HR 0.672, 95% CI: 0.514-0.878), and neoadjuvant chemotherapy (HR 0.431, 95% CI: 0.316-0.587) were associated with decreased risk of incomplete resection. The 5-year OS was 43.7% in the entire cohort and 28.8% in patients with positive margins and 47.5% in patients with an R0 resection. Positive margin was also associated with a significantly higher 90-day mortality rate (9.9% versus 6.7%)., Conclusions: For patients with large, node-negative NSCLC invading nearby structures, R0 resection portends better survival. Treatment at academic centers, adenocarcinoma histology, and receipt of neoadjuvant chemotherapy are associated with R0 resection in this high-risk cohort., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-989/coif). D.M. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2022 to September 2024. D.M. reports research support from Heat Biologics (Inst), Merck (Inst), Celgene (Inst), AstraZeneca (Inst), Baxter (Inst), Incyte (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), EpicentRx (Inst), Pfizer (Inst), Roche (Inst), Lilly (Inst), Altum Pharmaceuticals (Inst), Array BioPharma (Inst), Surface Oncology (Inst), Arcus Biosciences (Inst), Boehringer Ingelheim (Inst), Y-mAbs Therapeutics (Inst) and participation on a data safety monitoring board for AbbVie, G1 Therapeutics, Lilly Medical, Mirati Therapeutics, Arcus Biosciences. S.N.W. mentioned support from AbbVie Inc., Ariad Pharmaceuticals, Genentech, Immunomedics, Inc., Millennium Pharmaceuticals Inc., Roche, Astellas Pharma Inc., Daiichi Sankyo, Cullinan Pearl, Verastem Inc., GlaxoSmithKline/GSK, Janssen Research & Development, LLC, Elevation Oncology, Genentech, Loxo Oncology, Takeda Pharmaceuticals, Ribon Therapeutics, Inc., AstraZeneca Pharmaceuticals LP, Advenchen Laboratories, Gilead Sciences for the institution for clinical trials, SWOG-Clinical Trials Partnership, and receives payment for lectures or honoraria for ASCO SEP Editorial board, and she participates on the advisory board for AstraZeneca, Gilead Sciences, Janssen, and Hoosier Cancer Research Network. P.P.S. has speaking honoraria for Varian Medical Systems. B.T.H. is a former consultant at Oncocyte Corporation and a former MBA intern at Eli Lilly and Company. V.P. reports receiving NIH funding (R01CA258681). The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)