Ink-substrate adhesion critically impacts the print and page attributes of advanced printing technologies. Here the authors show that interfacial acid-base interaction (A-BI) plays an important role in the enhancement of ink-substrate adhesion. Successful probing of the ink-substrate interface via surface-sensitive attenuated-total-reflectance Fourier-transform infrared spectroscopy reveals intricate transient A-BI behavior, which appears to dominate the initial phase of adhesion in a printed substrate. The authors also demonstrate that macroscopic adhesion strength between an ink layer and a substrate can be correlated directly to the extent of A-BI. Their observation could potentially pave new directions for future advancement of high speed digital printing technology and could have important implications in other marking material systems.