Perfluorinated compounds (PFCs) are usually monitored by high performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on triple quadrupole instruments. Although not yet widely implemented in the field, high resolution mass spectrometry (HRMS) today appears as a valuable alternative for these halogenated chemicals due to their significant mass defect. Indeed, this second approach offers a way to cope with particular matrix effects caused by co-eluting and isobaric interferences affecting the measurement of some PFCs in fish. The present study has compared three different LC-MS related instruments and various signal acquisition modes, from low resolution full scan and selected ion monitoring (SIM) mode on triple quadrupole (QqQ) instrument to high resolution full scan or product ion scan mode on orbital trap (LTQ-Orbitrap) or quadrupole-time-of-flight (Q-TOF) devices. Performances have been compared for 7 model compounds belonging to 7 PFCs sub-classes (perfluoralkylsulfonate, perfluoroalkylcarboxylate, perfluoroalkylsulfinate, perfluoroalkyl-sulfonamide, fluorotelomer saturated acid, fluorotelomer unsaturated acid and perfluoroalkylphosphonic acid). Low resolution MS/MS was found to be unsurprisingly reliable for extended multiresidues monitoring. However, the high stability of PFCs leads to a relatively poor and non-specific fragmentation pathway in MS/MS. In addition, biliary acid interfering compounds (e.g. taurochenodeoxycholic acid), that where encountered in the present case in fish samples but that may be present in other biological samples, were found particularly disturbing in low resolution MS/MS. Indeed, these interferences presented the same retention time and diagnostic signals as PFOS, leading to a possible overestimation of the PFOS quantification in LC-MS/MS. On the other hand, high resolution MS and MS/MS (LTQ-Orbitrap and Q-TOF) provided better results in terms of signal specificity and sensitivity. For instance, the estimated limits of detection (LOD) reached for PFOS on QqQ, Q-TOF and LTQ-Orbitrap instruments were 3.8, 0.7 and 0.5 pg injected, respectively.