Owing to its imidazole side chain, histidine participates in various processes such as enzyme catalysis, pH regulation, metal binding, and phosphorylation. The determination of exchange rates of labile protons for such a system is important for understanding its functions. However, these rates are too fast to be measured directly in an aqueous solution by using NMR spectroscopy. We have obtained the exchange rates of the NH3+ amino protons and the labile NH epsilon 2 and NH1 protons of the imidazole ring by indirect detection through nitrogen-15 as a function of temperature (272K<T<293K) and pH (1.3<pH<4.9) of uniformly nitrogen-15- and carbon-13-labeled L-histidineHClH(2)O. Exchange rates up to 8.5x10(4)s(-1) could be determined (i.e., lifetimes as short as 12s). The three chemical shifts (Hi) of the invisible exchanging protons H-i and the three one-bond scalar coupling constants (1)J(N,H-i) could also be determined accurately.