Chemical exchange processes of proteins on the order of microseconds (pis) to milliseconds (ms) play critical roles in biological functions. Developments in methyl-transverse relaxation optimized spectroscopy (methyl-TROSY), which observes the slowly relaxing multiple quantum (MOD coherences, have enabled the studies of biologically important large proteins. However, the analyses of mu s to ms chemical exchange processes based on the methyl-TROSY principle are still challenging, because the interpretation of the chemical exchange contributions to the MQ relaxation profiles is complicated, as significant chemical shift differences occur in both H-1 and C-13 nuclei. Here, we report a new methyl-based NMR method for characterizing chemical exchanges, utilizing differential MQ relaxation rates and a heteronuclear double resonance pulse technique. The method enables quantitative evaluations of the chemical exchange processes, in which significant chemical shift differences exist in both the H-1 and C-13 nuclei. The versatility of the method is demonstrated with the application to KirBacl.1, with an apparent molecular mass of 200 kDa.