We have observed large matrix effects in the secondary ion emission from alloys when bombarded with an O+2 beam. Binary alloys of Ni with Cr, Fe, and Cu were studied. Chromium, which reacted most strongly with oxygen, induced the largest enhancement of the Ni+ ionization probability. Iron enhanced the Ni+ ionization probability to a lesser extent, whereas copper resulted in a decrease of the Ni+ ionization probability. Ni also induced a small enhancement of the ionization probability of Cr. We find a strong correlation of the mean free energy of formation of the metal‐oxide bond with the observed trends in the ionization probabilities. These matrix effects can cause artifacts in the depth profiling of metal film structures where interdiffusion at the interface leads to the formation of alloys or intermetallic compounds. This is indeed observed when interfaces of Ni–Fe and Ni–Cr films are studied by SIMS.