The influence of H2 flooding on the development of surface roughness during time-of-flight secondary ion mass spectrometry (ToF-SIMS) depth profiling was studied to evaluate the different aspects of a H2 atmosphere in comparison to an ultrahigh vacuum (UHV) environment. Multilayer samples, consisting of different combinations of metal, metal oxide, and alloy layers of different elements, were bombarded with 1 and 2 keV Cs+ ion beams in UHV and a H2 atmosphere of 7 × 10-7 mbar. The surface roughness Sa was measured with atomic force microscopy (AFM) on the initial surface and in the craters formed while sputtering, either in the middle of the layers or at the interfaces. We found that the roughness after Cs+ sputtering depends on the chemical composition/structure of the individual layers, and it increases with the sputtering depth. However, the increase in the roughness was, in specific cases, approximately a few tens of percent lower when sputtering in the H2 atmosphere compared to the UHV. In the other cases, the average surface roughness was generally still lower when H2 flooding was applied, but the differences were statistically insignificant. Additionally, we observed that for the initially rough surfaces with an Sa of about 5 nm, sputtering with the 1 keV Cs+ beam might have a smoothing effect, thereby reducing the initial roughness. Our observations also indicate that Cs+ sputtering with ion energies of 1 and 2 keV has a similar effect on roughness development, except for the cases with initially very smooth samples. The results show the beneficial effect of H2 flooding on surface roughness development during the ToF-SIMS depth profiling in addition to a reduction of the matrix effect and an improved identification of thin layers.