Direct selective sensing of arginine in central nervous systems remains very essential to understanding of the molecular basis of some physiological events. This study presents the first demonstration on a simple yet effective method for arginine sensing with gold nanoparticles (Au-NPs) as the signal readout. The rationale for the method is based on the pH-dependent feature of the interionic interaction between cysteine and arginine. At pH 6.0, cysteine can only interact with arginine through the ion-pair interaction and such interaction can lead to the changes in both the solution color and UV-vis spectrum of the cysteine-protected Au-NPs upon the addition of arginine. These changes are further developed into an analytical strategy for effective sensing of arginine by rationally controlling the pH values of Au-NP dispersions with the ratio of the absorbance at 650 nm (A (650)) to that at 520 nm (A (520)) (A (650)/A (520)) as a parameter for analysis. The method is responsive to arginine without the interference from other species in the cerebral system; under the optimized conditions, the A (650)/A (520) values are linear with the concentration of arginine within a concentration range from 0.80 to 64 mu M, yet remain unchanged with the addition of other kinds of amino acids or the species in the central nervous system into the Au-NPs dispersion containing cysteine. The method demonstrated here is reliable and robust and could thus be used for detection of the increase of arginine in central nervous systems.