The 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 M W ≥ 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 R SW (12-20 km) and the long-wavelength roughness R LW (80-100 km). We observe that ruptures with M W ≥ 7.5 tend to occur preferentially on smooth subducting seafloor at long wavelengths, which is especially clear for the M W > 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. Plain Language Summary Subduction zones are regions on Earth where an oceanic plate dives below another plate. Earthquakes that occur along the contact between plates in such regions are among the largest and most destructive on Earth. To better understand where these large earthquakes are most likely to occur, we look at the effect of seafloor roughness. A rough seafloor is often characterized by many topographic features, such as seamounts or ridges, while a smooth seafloor is generally more flat. On a global scale, we compared the roughness of the incoming seafloor of the downgoing plate, with the occurrence of large earthquakes in each subduction zone. We find that the seafloor in front of large earthquakes is generally smoother than in areas where no large earthquakes have occurred. This is the clearest for very large earthquakes, with magnitudes larger than 8.5. Investigating which parameters play a role in the location of earthquakes helps us to understand where future earthquakes are more likely to occur.