The effects of high pressure on the structural stability of the melamine-boric acid adduct (C3N6H(6).2H3BO3, M.2B), a three-dimensional hydrogen-bonded supramolecular architecture, were studied by in situ synchrotron X-ray diffraction (XRD) and Raman spectroscopy. M.2B exhibited a high compressibility and a strong anisotropic compression, which can be explained by the layerlike crystal packing. Furthermore, evolution of XRD patterns and Raman spectra indicated that the M.2B crystal undergoes a reversible pressure-induced amorphization (PIA) at 18 GPa. The mechanism for the PIA was attributed to the competition between close packing and long-range order. Ab initio calculations were also performed to account for the behavior of hydrogen bonding under high pressure.