While high-resolution MS (HRMS) can be used for identification and quantification of novel per- and polyfluorinated alkyl substances (PFAS), low-resolution MS/MS is the more commonly used and affordable approach for routine PFAS monitoring. Of note, perfluoropentanoic acid (PFPeA) and perfluorobutanoic acid (PFBA), two of the smaller carboxylic acid containing-PFAS, have only one major MS/MS transition, preventing the use of qualitative transitions for verification on low-resolution instrumentation. Recently our lab has observed widespread chemical interference in the quantitative ion channel for PFPeA (263 → 219) and PFBA (213 → 169) in numerous matrices. PFPeA interference was investigated using HRMS and putatively assigned as a diprotic unsaturated fatty acid (263.1288 Da) in shellfish and a separate interferent (13C isotope of 262.1087 Da) in hot cocoa, which had been previously described by the FDA. PFBA interference caused by saturated oxo-fatty acids, previously demonstrated in tissue, was also observed in liquid condensate from a residential air conditioning unit. Therefore, in support of PFAS analysis on low-resolution instrumentation, authors recommend several adjustments to analytical methods including altering liquid chromatography (LC) conditions as well as using matched internal standards to investigate and expressly confirm PFBA and PFPeA detections in both biological and environmental samples.