Mass spectrometry (MS) is a highly sensitive analytical technique that is o en coupled with liquid chromatography (LC). However, some bu ering salts used in LC (e.g., phosphate and tris(hydroxymethyl) aminomethane (Tris)) are incompatible with MS since they cause ion-source contamination and signal suppression. In this study, we examined salt tolerance of MALDI and applied a matrix additive methylenediphosphonic acid (MDPNA) to reduce salt-induced signal suppression. MDPNA signi cantly improved the salt tolerance of MALDI-MS. Using ammonium formate bu er at pH 5.0, the e ective range of bu ering salt concentration in MALDI-MS using MDPNA was estimated up to 250 mM. MDPNA reduced signal suppression caused by bu ering salts at pH 4.0 to 8.0. We observed that MDPNA e ectively worked over a wide range of bu er conditions. MDPNA was further applied to hydrophilic interaction chromatography (HILIC) and chromatofocusing-MALDI-MS. As a result, the analytes in the eluent containing high-concentration salts were detected with high sensitivity. us, our study provides simple and fast LC-MALDI-MS analysis technique not having strict limitation of bu ering condition in LC by using matrix additive MDPNA.