A total of 481,414 Korean participants aged 40-79 years at enrollment were examined. The hazard ratios for all-cause, all-cancer, and head and neck cancer mortality were analyzed using Cox proportional hazards models, which were adjusted for potential confounding factors. In the overall study population, the highest AST/ALT ratio level was significantly associated with risk of all-cause, all-cancer, and head and neck cancer mortality (p < 0.01). After excluding participants who died of all-cause, all-cancer, and head and neck cancer within five years of enrollment, the main results remained similar to those of the analysis of all deaths in the study population. These findings indicate that serum AST/ALT ratio is positively associated with an increased mortality risk in all-cause, all-cancer, and head and neck cancer.