This study focused on the role of the AST/ALT ratio in patients with HNSCC. We found that the AST/ALT ratio had no significant associations with T and N classifications and was an independent prognostic factor for overall survival. In addition, we validated the prognostic effect of the AST/ALT ratio with the independent data set. The AST/ALT ratio further divided patients with stage IVA into poorer and better prognosis subsets.