Background: HER2 mutations are identified in about 2% of non-small cell lung cancer (NSCLC) and behave as an oncogenic driver. Little is known about the efficacy of chemotherapy and of HER2 targeted drugs in this population. We aimed to study therapeutic outcomes of patients harboring HER2 mutations (HER2+) in order to establish the efficacy of various drug regimens and to orient future clinical trials. Methods: We conducted a retrospective cohort study in European centers testing NSCLC patients for HER2. Eligible patients had advanced stage NSCLC, known HER2 exon 20 insertions by local testing, and treatment with chemotherapy and/or targeted drugs. Clinicians had to obtain informed consent and IRB approval according to local regulations, and response were assessed according to RECIST version 1.1. Data were anonymized and analyzed centrally. Results: We identified 101 eligible patients from 38 centers. Our population was characterized by a median age of 61 yrs (30-87), a high proportion of women (63 vs. 38 men, 62.4%), and of never smokers (61, 60.4%). All tumors were adenocarcinomas. Concomitant EGFR mutation, ALK translocation and ROS translocation were observed in 5, 1 and 1 patients respectively. The median number of treatment lines was 3 (1-11). Overall survival of the whole population (n = 101) was 24 months (m.). Response rate (RR) and median progression free survival (PFS) for patients treated with conventional chemotherapy (excluding targeted therapy) were 43.5% and 5.9 m. in first line (n = 93) and 10% and 4.2 m. in second line (n = 52) respectively. RR to EGFR-TKI (n = 27) was 7.2% and PFS was 3 m. Eighty-six targeted treatments against HER2 were given to 65 patients including trastuzumab (n = 57), neratinib (n = 14), afatinib (n = 9), lapatinib (n = 5) and T-DM1 (n = 1). RR was 18% and PFS 3.9 months for afatinib. RR was 50% and PFS 5.1 m. for trastuzumab (given with vinorelbine n = 24, docetaxel n = 12, paclitaxel n = 12, cisplatinum based combination n = 7, alone n = 2). Conclusions: This series, the largest to date, underlines the chemosensitivity of HER2 + NSCLC and the potential interest of anti-HER2-antibodies that deserve to be further evaluated in clinical trials.