We observe that pressure-induced amorphization of Ga2SeTe 2 (a III-VI semiconductor) is directly influenced by the periodicity of its intrinsic defect structures. Specimens with periodic and semi-periodic two-dimensional vacancy structures become amorphous around 10-11 GPa in contrast to those with aperiodic structures, which amorphize around 7-8 GPa. The result is an instance of altering material phase-change properties via rearrangement of stoichiometric vacancies as opposed to adjusting their concentrations. Based on our experimental findings, we posit that periodic two-dimensional vacancy structures in Ga2SeTe2 provide an energetically preferred crystal lattice that is less prone to collapse under applied pressure. This is corroborated through first-principles electronic structure calculations, which demonstrate that the energy stability of III-VI structures under hydrostatic pressure is highly dependent on the configuration of intrinsic vacancies. © 2014 AIP Publishing LLC.