An understanding of the response of nanomaterials to specific environmental parameters is an essential prerequisite for their practical use, especially in living systems. Herein, we disclose the preparation of a watersoluble nanocluster Au-16(SR)(12) (SR denotes deprotonated captopril) and its characterization by a combination of theoretical (e.g., density functional theory calculations) and experimental (UV-vis, electrospray ionization mass spectrometry, etc.) methods. Interestingly, Au-16(SR)(12) was found to convert to Au-18(SR)(14) under acidic conditions, while the reverse conversion from Au-18(SR)(14) to Au-16(SR)(12) occurred upon the addition of base. A mechanistic investigation determined this pH regulation to originate from the distinct steric and electrostatic properties of these two clusters. This study is the first to report the susceptibility of Au-18(SR)(14) and Au-16(SR)(12) to pH, and the distinct pH stability unambiguously reveals the importance of size-tracking of nanomaterials in living systems for future clinical applications.