As a part of our study on the use of isotopic analogues as the internal standard (IS) for the quantitation of drug analytes, this article reports on the performance characteristics of 2H5-butalbital and 13C4-butalbital with particular focus on (1) determining and comparing the effectiveness of the 2H- and 13C-analogues in serving as the ISs for quantitation; (2) understanding the “cross-contribution” phenomenon underlying the effectiveness of selected ion pairs used for quantitation purpose; and (3) examining whether the same characteristics, observed in our preliminary report for the secobarbital/2H5-secobarbital/13C4-secobarbital system, also exist in the butalbital/2H5-butalbital/13C4-butalbital system. Adapting similar procedures applied to our previous study on the secobarbital system, we observed that (1) both labeled analogues (13C4-butalbital and 2H5-butalbital) cause more significant cross-contributions to ions designated for butalbital than butalbital to the labeled analogues; (2) compared to 2H5-butalbital, 13C4-butalbital appears to cause less cross-contributions to ions designated for butalbital; (3) cross-contribution between the following ion pairs are minimal: m/z 200/196, 199/195, 185/181 (13C4-butalbital as the IS) and m/z 201/196 (2H5-butalbital as the IS). It is also concluded that the butalbital/2H5-butalbital system exhibits the same concentration dependency phenomenon observed in the secobarbital/ 2H5-secobarbital system, that is, ratios of ion pairs designated for these two isotopic analogues (resulting from routine gas chromatography–mass spectrometry protocol) increase as their concentrations are diluted. (In parallel with the secobarbital/ 13C4-secobarbital system, the butalbital/13C4-butalbital system does not exhibit this phenomenon.)