Sputter-initiated resonance ionization spectroscopy (SIRIS) is a very selective and extremely sensitive technique to analyze semiconductor materials. In the SIRIS technique, the abundant neutral atoms released by the sputtering process are ionized by precisely tuned laser beams and counted in a mass spectrometer. The resonance ionization spectroscopy (RIS) process virtually eliminates isobaric and other interferences and reduces matrix effects dramatically. Depth profiles of Si and In were measured in unannealed and rapid-thermal annealed SiO2–InP samples using the SIRIS and secondary ion mass spectrometry (SIMS) techniques. The results show diffusion process of In through the SiO2 layer and of Si into the InP substrate, as well as the matrix independence of the SIRIS technique. A detection limit, defined as 2 standard deviation above background, of In in Si was measured at 300 parts per trillion (ppt) with a 0.75 μA, 0.8 μs wide ion beam pulse and less than 3 min analysis time at 30 Hz repetition rate. Therefore, a detection limit in the low ppt range could be achieved with a 5 μA ion beam current and 25 min analysis time.