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A pair of stable isotope labeling (SIL) reagents, <b>N</b>-(4-(carbazole-9-yl)-phenyl)-<b>N</b>-maleimide (NCPM-d0) and its heavy analogue NCPM-d2, were used for labeling thiol-containing drugs. On basis of SIL, a global isotope internal standard quantitative method for the detection of five thiol-containing drugs by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed. The NCPM-d0 and NCPM-d2 can easily label thiol-containing drugs under mild conditions within 10 min at 40 °C. The NCPM-d0 and NCPM-d2 labeled thiol-containing drugs can generate two characteristic product ions (<b>m</b>/<b>z</b> at 372.5 and 374.5) under collision induced dissociation, respectively, which is used to establish the multiple reaction monitoring (MRM) based detection. The NCPM labeling combined with MRM analysis not only allowed trace detection of thiol-containing drugs due to the extremely high sensitivity, but also efficiently corrected the matrix effects during HPLC-MS/MS and the instrument fluctuation in the MS/MS signal intensity. The detection sensitivities of thiol-containing drugs improved by 14.5-650.5-fold due to NCPM-labeling, while the matrix and ion suppression effects were markedly minimized by the SIL strategy. The limits of detection (LODs) and the limits of quantitation (LOQs) were in the range 10.0-15.0 ng·mL−1 and 31.0-50.0 ng·mL−1, respectively. The proposed method was used for the simultaneous determination of five thiol-containing drugs in plasma samples with satisfactory recoveries in the range of 95.0-97.5%.<br>• A stable isotope labeling strategy for analyzing thiol-containing drugs has been developed. • A pair of SIL reagents NCPM-d0 and NCPM-d2 were used to label thiol-containing drugs. • The detection sensitivities of thiol-containing drugs improved by 14.5-650.5-fold. • The proposed method was successfully applied to pharmacokinetic study of captopril.