Seismicity patterns offshore Costa Rica (Central America) at the Middle America Trench have led to speculation that large (moment magnitude, Mw ∼7.0) earthquakes are associated with subducting topographic highs. In areas of high basement topography, a regionally extensive nannofossil chalk unit is exposed at the seafloor on the incoming plate, whereas in regions of low basement topography, hemipelagic clay-rich sediment is exposed. Because the entire sediment section is subducted at this margin, lithologic variation in the uppermost subducting sediments may control plate boundary fault behavior. Our laboratory experiments reveal that the chalk is frictionally strong (µ = 0.71–0.88) and characterized by velocity-weakening and stick-slip behavior, notably at elevated temperature. In contrast, the hemipelagic sediment is weak (µ = 0.22–0.35) and in many cases velocity strengthening. We suggest that the presence of frictionally unstable carbonates at bathymetric highs may play a key, previously unrecognized, role in governing earthquake nucleation.