The methylmercury ion (CH3Hg+) demonstrated a high efficiency for directly labeling peptide/protein based on its specific and strong interaction with the sulfhydryl(s) in the peptide/protein and because of its smallest size among monofunctional organic mercurials studied, including methylmercury, ethylmercury, 4-(hydroxymercuric)benzoic acid, and 2,7-dibromo-4-hydroxymercurifluoresceine disodium. A simple 1:1 stoichiometry between CH3Hg+ and sulfhydryl, confirmed with electrospray ionization-mass spectrometry (ESI-MS) and matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) studies, made it easy to calibrate the stoichiometry of Hg in the peptide/protein. In order to avoid the direct use of the harmful CH3Hg+, in this study a CH3Hg+-equivalent tag, methylmercurithiosalicylate (CH3Hg-THI), and its 204Hg-enriched homologue (CH3204Hg-THI) were synthesized, and then CH3Hg+ and/or CH3204Hg+ released from CH3Hg-THI and/or CH3204Hg-THI in solution were utilized to demonstrate the dynamic labeling of glutathione (GSH) and two model proteins, β-lactoglobulin (BLG) and ovalbumin (OVA), for the first time. Furthermore, the CH3204Hg-THI isotopical labeled GSH, BLG, and OVA standards (CH3204Hg-GSH, CH3204Hg-BLG, and CH3204Hg-OVA) were used to demonstrate the feasibility of absolute peptide/protein quantification using label-specific isotope dilution inductively coupled plasma mass spectrometry (ICPMS). On the basis of the accurate and sensitive determination of Hg using ICPMS, the detection limits of GSH, BLG, and OVA could reach 45.4, 45.4, and 15.1 pmol L−1, respectively, suggesting the possibility for low-abundance peptide/protein quantification alongside the surefire quantification of moderate and highly abundant peptide/protein.