For more than three decades, time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been used for elemental depth profiling. In recent years, cluster primary ion sources (principally, C60+, Bin+, and Aun+) have become widely available, and they can greatly enhance the signal intensity of molecular ions (10–1000 times). Understanding the performance of cluster ion analysis beams used in elemental depth profiling can greatly assist normal ToF-SIMS users in choosing the optimal analysis beam for depth profiling work. Presently, however, the experimental data are lacking, and such choices are difficult to make. In this paper, hydrogen and deuterium depth profiling were studied using six different analysis beams—25 keV Bi+, Bi3+, Bi5+, 50 keV Bi32+, 10 keV C60+, and 20 keV C602+. The effort shows that cluster primary ions do enhance H− and D− yields, but the enhancement is only about 1.5–4.0 times when compared to atomic Bi+ ions. Because the currents of atomic ion analysis beams are much stronger than the currents of cluster ion analysis beams for most commercial ToF-SIMS instruments, the atomic ion analysis beams can provide the strongest H− and D− signal intensities, and may be the best choices for hydrogen and deuterium depth profiling. In addition, two representative nuclides, 30Si and 18O, were also studied and yielded results similar to those of H− and D−. Copyright © 2011 John Wiley & Sons, Ltd.