Abstract: Adenocarcinoma and small cell carcinoma were two common pathological types of lung cancer. The clinical data, pathological, immunohistochemical and genetic test results of two patients with small cell lung cancer (SCLC) after lung adenocarcinoma were reported. One case of SCLC transformation of epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitor (TKI) after treatment occurred. Another one case was synchronous multiple primary lung cancer, and the two cases were compared based on the literature. The prognosis of the two cases was poor, but the definite diagnosis and difference between them needed further exploration, and neuron specific enolase (NSE) may have predictive value for recurrent SCLC.