Background: Although isolated locoregional recurrence (iLR) for non-small cell lung cancer (NSCLC) is relatively common, the optimal therapy for iLR is undefined. It is feasible that patients with iLR may have equal or superior outcomes to patients with de novo locally advanced NSCLC (LA-NSCLC). Herein, we present outcomes of patients with iLR vs. LA-NSCLC treated with definitive therapy. Methods: Patients with NSCLC treated with definitive radiotherapy between 2008–2018 at a tertiary academic center were identified, and patients with iLR were Abstracted. Inclusion criteria for iLR included patients with stage I–III NSCLC treated with curative intent, with subsequent iLR that was treated again with definitive therapy. iLR was defined as any recurrence within the ipsilateral lung and the N1–N3 nodal groups. For comparison, patients with de novo LA-NSCLC were extracted from an existing institutional database. Univariate Cox proportional hazards model was used to compare outcomes and clinical characteristics. PFS, OS, and time to distant metastasis (TTDM) were calculated using Kaplan-Meier methodology and compared using the log-rank test. Results: Of 2053 definitively dosed thoracic radiation records accessed, 94 patients had iLR NSCLC. 59 patients met inclusion criteria and were compared to 303 patients with de novo LA-NSCLC. Baseline characteristics were not significantly different between groups. The majority of patients with iLR had original stage I disease (n=34), were initially treated with surgery (n=31) or SBRT (n=13) alone, and had stage rIIIA at recurrence (n=41). Most patients were offered definitive salvage chemoradiotherapy or trimodality therapy. On univariate analysis for iLR, targetable mutations had significantly worse PFS (HR 1.65) and TDDM (HR 1.86), while squamous histology had a significantly worse OS (HR 1.44). The median PFS (17.0 vs. 11.6 months) and TTDM (35.7 vs. 25.9 months) was not significantly different between iLR and LA-NSCLC patients, respectively. OS differed significantly between groups (iLR=49.9 months, LA-NSCLC=29.8 months, p=0.02). Conclusions: This is the first study to compare a controlled cohort of patients with iLR NSCLC to a de novo equivalent. In patients treated with definitive intent, outcomes in those with iLR compared similarly to patients with LA-NSCLC. This data supports the use of aggressive combined modality treatment in lieu of systemic therapy alone for patients with locally recurrent disease.