Two analgesic and antiinflammatory drugs, antipyrine and propyphenazone, were investigated with infrared laser desorptiontunable synchrotron vacuum ultraviolet VUV photoionization mass spectrometry IR LDVUV PIMS and theoretical calculations. Mass spectra of the two drugs were measured at various photon energies. Fragment ions were gradually produced as photon energy increases. The structural assignment of the dominant fragment ions was supported by the results from a commercial electron impact timeofflight mass spectrometer EITOF MS. Primary fragmentation pathways were established from experimental observations combining with theoretical calculations. Methyl radical elimination is a common fragmentation pathway for two analytes. However, for propyphenazone cation, isopropyl group elimination to form antipyrine cation is another competitive pathway. Copyright © 2010 John Wiley & Sons, Ltd.