An underivatized methane chemical ionization (CI) assay for measuring amphetamines in urine was evaluated against derivatized electron impact (EI) assays using a gas chromatograph-ion trap mass spectrometer. The full-scan CI mass spectra of methamphetamine, ephedrine/pseudoephedrine, and phentermine were compared with the full scan and three-ion EI mass spectra of heptafluorobutyric anhydride (HFBA) and 4-carbethoxyhexafluorobutyryl chloride (CB) derivatives. The fragmentation patterns for these compounds were nearly identical for the three major high molecular weight ions (m/z 254, 210, and 169 for EI-HFBA derivatives, and m/z 308, 262, and 280 for EI-CB derivatives). The CI mass spectra of the underivatized drugs contained more discernible differences at the higher molecular weights, including m/z 119, 148, and 150 for methamphetamine, 148, 166, and 176 for ephedrine/pseudoephedrine, and 91, 133, and 150 for phentermine. The within-run precision ranged from 7–9% for CI versus 5–6% for EI with HFBA derivatization (mean 500 ng/mL, n = 5). The limits of detection (LOD) for amphetamine and methamphetamine were 2.4 and 8.6 ng/mL, respectively, for CI versus 0.7 and 1.4 ng/mL for EI. The limits of quantltatlon (LOQ) were 4.5 and 19.1 ng/mL for CI versus 1.4 and 5.7 ng/mL for EI. The use of full-scan mass spectral analysis with either electron impact or chemical ionization provides additional qualitative data that may be helpful for measuring methamphetamine in the presence of other sympathomimetic amines.