The use of perfluorinated anhydrides coupled with perfluoroalcohols for the derivatization of cannabinoids has been well documented. Derivatization is used in the detection of cannabinoids using gas chromatography-mass spectrometry (GC-MS) with both electron impact ionization (EI) and negative chemical ionization (NCI). During method development for the analysis of cannabinoids in biological samples using GC-MS in EI and NCI mode, it was observed that when Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) were derivatized with trifluoroacetic anhydride (TFAA), the resultant derivatives produced the same retention times and mass spectra. This was not observed with the trimethylsilyl (TMS) derivatives of THC and CBD. This complication is due to the conversion of CBD to THC under acidic conditions. The work here highlights the unsuitability of the derivatizing reagent TFAA for the detection of THC and CBD. For the analysis of case samples, even if only THC is of interest, the presence of CBD cannot be excluded, and other derivatization techniques should be used.