AbstractThe role of seafloor roughness on the seismogenic behavior of subduction zones has been increasingly addressed over the past years, although their exact relationship remains unclear. Do subducting features like seamounts, fracture zones, or submarine ridges act as barriers, preventing ruptures from propagating, or do they initiate megathrust earthquakes instead? We address this question using a global approach, taking into account all oceanic subduction zones and a 117‐year time window of megathrust earthquake recording. We first compile a global database, SubQuake, that provides the location of a rupture epicenter, the overall rupture area, and the region where the largest displacement occurs (the seismic asperity) for MW ≥ 7.5 subduction interplate earthquakes. With these data, we made a quantitative comparison with the seafloor roughness seaward of the trench, which is assumed to be a reasonable proxy for the subduction interface roughness. We compare the spatial occurrence of megathrust ruptures, seismic asperities, and epicenters, with two roughness parameters: the short‐wavelength roughness RSW (12–20 km) and the long‐wavelength roughness RLW (80–100 km). We observe that ruptures with MW ≥ 7.5 tend to occur preferentially on smooth subducting seafloor at long wavelengths, which is especially clear for the MW > 8.5 events. At both short and long wavelengths, seismic asperities show a more amplified relation with smooth seafloor than rupture segments in general. For the epicenter correlation, we see a slight difference in roughness signal, which suggests that there might be a physical relationship between rupture nucleation and subduction interface roughness.