BACKGROUND: The fat mass and obesity-associated protein (FTO) is implicated in various diseases and acts as a demethylase for the most abundant modification of mRNA, namely N6-methyladenosine (m METHODS: Using immunohistochemistry, quantitative real-time polymerase chain reaction (RT-qPCR), and Western blot analysis, we compared the expression levels of FTO in HSCC tissues to adjacent non-cancerous tissues. Furthermore, we evaluated the prognosis of patients with hypopharyngeal cancer in relation to FTO expression levels. RESULTS: The results showed that FTO was highly expressed in hypopharyngeal cancer tissues and was correlated with clinicopathology of patients. FTO promoted the proliferation, invasion and migration of hypopharyngeal cancer cells CONCLUSIONS: Our study highlighted the functional significance of the FTO/SERPINE1 axis in tumorigenesis of HSCC. Targeting FTO holds promise as a new therapeutic strategy for HSCC.