With the rapid development of detection methods, next-generation sequencing (NGS) technology as a new technology, some novel epidermal growth factor receptor (EGFR) gene fusions comprising the EGFR linked to various fusion partners, most commonly RAD51, are detected in the non-small cell lung cancer (NSCLC). We described a case of an unreported kinesin family member 5B (KIF5B)-EGFR in NSCLC and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) to this specific fusion. Considering this rare EGFR fusion and remarkable response to EGFR-TKI, we should realize the importance of these rare EGFR fusions, the advances in diagnostic techniques and personalized care for lung cancer patients.