Applicability of atmospheric pressure photoionization mass spectrometry (APPI-MS) to the analysis of hydrophilic drugs was investigated. Model compounds with moderate to high hydrophilicity was tested, and most compounds showed good signal response with APPI-MS, but some compounds with high molecular polarity like folic acid derivatives, glycoside and some nucleic acid derivatives showed very weak signal responses. By observing relationship between the compounds' physicochemical properties and APPI response, compounds with higher lipophilicity and less polar surface area were considered to be advantageous for APPI-MS. To provide information for applying APPI-MS to the analysis of hydrophilic drugs, approximate lower limit of calculated octanol-water partition coefficient and the higher limit of the number of oxygen and nitrogen atoms were determined to be -0.95 and 6, respectively. These APPI-applicable model compounds could be analyzed by reversed-phase high performance liquid chromatography-APPI-tandem mass spectrometry.