We introduce a new reagent – Trimethylacetic anhydride (TMA) for highly efficient histone derivatization, which is facilitated by microwave irradiation to reduce sample preparation duration. The derivatization of unmodified NH2- groups at histone lysine residues is necessary prior LC-MS analysis using bottom-up approach. Our methodology shows high labelling efficiency and demonstrates its utilization for histone posttranslational modification abundance monitoring. Therefore, to be an alternative to conventionally used methods.