Cetuximab was approved in Japan as the only clinically available molecular targeted drug for the treatment of head and neck cancer. Hypomagnesemia associated with cetuximab is considered one of the most serious adverse events. However, the factors influencing the development of hypomagnesemia are not clear, although the drug was previously approved for the treatment of patients with colorectal cancer. Thus, we studied the factors involved in the development of hypomagnesemia in patients receiving cetuximab therapy for head and neck cancer. Patients' background data and laboratory values before starting cetuximab therapy did not affect the development of hypomagnesemia. Among patients who had never been treated with cisplatin (NT group), 36.4% developed hypomagnesemia. In contrast, all patients who had previously been treated with cisplatin (T group) developed hypomagnesemia (p=0.034). Magnesium is reabsorbed by transient receptor potential subfamily melastatin 6 (TRPM6) in the distal convoluted tubule. The expression level of TRPM6 is controlled by the epidermal growth factor (EGF) pathway. Cetuximab is an EGF receptor inhibitor and reduces the expression of TRPM6. Additionally, recent studies have shown that the expression of TRPM6 is reduced by cisplatin. Therefore, we considered that the serum magnesium level was cumulatively reduced by cetuximab and cisplatin. In conclusion, the T group was more likely to develop hypomagnesemia than the NT group, and therefore the serum magnesium level in the T group requires careful monitoring so that magnesium supplementation can be provided to patients when the level decreases.