Background: Patients with early onset lung cancer might be more likely to carry pathogenic (or likely-pathogenic) germline variants (PGV) in genes associated with cancer predisposition. However, germline testing is not recommended in this population. We designed this study to determine the prevalence of PGVs in patients with early onset lung cancer. Methods: This prospective, multicenter cohort study assessed PGV in patients younger than 51 years diagnosed with non-small cell lung cancer (NSCLC) in 3 sites at the Catalan Institute of Oncology between June 2018 to May 2022. Genomic DNA was sequenced using a custom-designed NGS panel covering 164 cancer-predisposing genes and results were discussed in a multidisciplinary tumor board. Results: 138 patients were included. Median age was 45.5 (28-50) years; 49% were females; 79% were ever-smokers with a median packs-year of 24 and median age of tobacco initiation of 16 years old. Most patients had non-squamous histology (88%) and had stage IV (62%) at diagnosis. Somatic oncogenic drivers were found in 74 patients (54%): EGFR 27 (20%); ALK 22 (16%); KRAS 20 (14%); RET 3 (2%); ROS1 1 (1%); BRAF V600E 1 (1%). Only 4% had past personal history of cancer and 50% had family history of cancer in a first-degree relative, being lung and breast cancer the most common tumors. Overall, 20 patients (14%) carried PGVs involving 12 genes associated with cancer predisposition: PARK2 (n=4); SBDS (n=3); NBN (n=2); ATM (n=2); TSC1 (n=2) and BLM, FANCA, MCPH1, PMS2, POLH, SDHA, RECQL4 (n=1, each). Four patients (3%) fulfilled criteria to be referred to genetic counseling clinic. There were no significant differences in clinical and molecular characteristics among patients with PGVs compared to their counterparts (Table). Conclusions: In this prospective cohort, 14% of patients with early onset NSCLC harbored germline PGVs. As clinicopathological and genomic features were not associated with PGVs, germline testing might be considered in addition to comprehensive genomic characterization of tumor tissue in young patients with NSCLC. However, only a minority of PGVs were deemed clinically actionable.