Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the treatment of advanced non-small cell lung cancer. However, patients will inevitably develop resistance to EGFR-TKIs in the long-term treatment process. In this paper, we report a case of small cell lung cancer transformation after EGFR-TKIs treatment in lung adenocarcinoma. We summarize the characteristics of this case and the treatment after transformation, and emphasized the repeat biopsy and dynamic monitoring its genetic mutation was necessary.A 75-years-old man with no smoking history was admitted to our hospital with repeated cough and expectoration for 1 month and chest enhancement computed tomography showed paracbronchial soft tissue mass in the lower lobe of the left lung, which was considered to be central lung cancer.The first pathological analysis of lung biopsy confirmed left lung adenocarcinoma and clinical stage was T3N3M1 IVA. In June 2021, the second bronchoscopic biopsy was performed, and pathology showed small cell neuroendocrine carcinoma in the left lung.Gefitinib was given to patients when the first next generation sequence test showed EGFR L858 mutation. When the second next generation sequence test revealed EGFR T790M mutation, the patient received with osimertinib. The patient got 2 cycles chemotherapy of etoposide plus netaplatin when diagnosed with small cell lung cancer.Progression-free survival was only 8 months after gefitinib treatment. Moreover, the patient was insensitive to Oxitinib, and the disease progressed after 2 months of treatment with Oxitinib. Finally, he died of severe infection and hepatic failure after a diagnosis of small cell lung cancer.Our case highlights that if a patient has rapid disease progression, increase of serum neuron-specific enolase, and TP53 and Rb1 inactivation during EGFR-TKIs treatment, we should be alert to the pathological type transformation to small cell lung cancer.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.