Background: Mutation of human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) is a rare event, found in approximately 1% non-small cell lung cancers (NSCLC). The objective was to investigate the clinical characteristics and management of HER2-mutated NSCLCs in a real-life setting. Methods: This multicenter study described NSCLCs harboring HER2 mutations diagnosed between January 2012 and December 2014, according their clinical characteristics, management, and outcomes: response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Thirty patients were included: 66.7% women; median age 65.2 ± 12 years; never or former smokers 73.3%. Of the stage IV patients (n = 23), 86% received first-line platin doublet chemotherapy: RR 61.5% and PFS 6.7 (95% CI 5.9-9.5) months; 52.1% received a second-line therapy: RR 18.2% and PFS 4.9 (95% CI 2.5-11.9) months. Median OS of stage IV was 10.7 months and 2-year OS was 27.2% (95% CI 11.7-63.2). All patients with stage I-III NSCLCs were alive at 2 years. Conclusion: The rarity of HER2-mutated NSCLCs requires specific studies. Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.8138837.