IMPORTANCE: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. OBJECTIVE: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS: Chemoradiation and consolidation chemotherapy with or without metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02186847.