RAS mutations constitute one of the major tumorigenic mechanisms and are detected in approximately 20% of lung cancers. The most frequent mutated and well-studied RAS isoform is KRAS, which is associated with an overall poor prognosis in non-small-cell lung cancer (NSCLC). However, the clinical significances of NRAS and HRAS in NSCLC are rarely reported. Here, we present a 58-year-old male smoker who was diagnosed with stage IV lung adenosquamous carcinoma. A rare NRAS and HRAS double mutation was detected in the primary tumor and lymph node samples using next-generation sequencing (NGS). The patient showed rapid disease progression and passed away due to respiratory failure after 15 days of osimertinib in combination with cisplatin. To the best of our knowledge, this is the first report associating NRAS and HRAS double mutation in the poor prognosis of NSCLC. © 2021 Zhao et al.