Driver mutations involving tyrosine kinase receptors play crucial roles in the oncogenesis of lung adenocarcinoma. However, receptor tyrosine kinase mutations are extremely rare events in primary pulmonary neuroendocrine carcinoma (NEC), which is a molecular heterogeneous entity. In this study, we examined 4 cases of NEC with anaplastic lymphoma kinase (ALK) rearrangement between 2008 and 2018 at our hospital. We comprehensively analyzed the carcinomas' clinicopathological features, genetic alterations, and response to ALK inhibitor. One case of atypical carcinoid tumor and 1 case of large cell NEC (LCNEC) achieved response to ALK inhibitor (crizotinib) treatment. One case of combined LCNEC with adenocarcinoma harboring KLC1-ALK (K9:A20) fusion genes was confirmed by NGS of both components, while only the LCNEC component presented RB1 mutation. Notably, tumor cells of different components exhibited different ALK-positive signal patterns by fluorescence in situ hybridization, which revealed isolated 3' signals in the adenocarcinoma component but split signals in the LCNEC. As the largest case series study, our findings suggested that preliminary screening for ALK rearrangement should also be considered in atypical carcinoid and high-grade NEC. Patients with ALK rearrangement-positive NEC would benefit from ALK inhibitor intervention.