It is a common knowledge that detector fatigue causes a calibration curve to deviate from the preferred linear relationship at the higher concentration end. With the adaptation of an isotopically labeled analog of the analyte as the internal standard (IS), cross-contribution (CC) of the intensities monitored for the ions designating the analyte and the IS can also result in a non-linear relationship at both ends. A novel approach developed to assess 'the extent and the effect of [CC]… in quantitative GC-MS analysis' can be extended (a) to examine whether a specific set of CC values is accurate; and (b) to differentiate whether the observed non-linear calibration curve is caused by detector fatigue or the CC phenomenon. Data derived from the exemplar secobarbital (SB)/SB-d(5) system (as di-butyl-derivatives) are used to illustrate this novel approach. Comparing the non-linear nature of calibration data that are empirically observed to that derived from theoretical calculation (with the incorporation of adjustment resulting from the ion CC phenomenon), supports the conclusions that (a) both CC and detector fatigue contribute significantly to the observed non-linear nature of the calibration curve based on ion-pair m/z 207/212; and (b) detector fatigue is the dominating contributor when the calibration curve is based on ion-pair m/z 263/268.