Hydrologic loads can stimulate seismicity in the Earth’s crust1. However, evidence for the triggering of large earthquakes remains elusive. The southern San Andreas Fault (SSAF) in Southern California lies next to the Salton Sea2, a remnant of ancient Lake Cahuilla that periodically filled and desiccated over the past millennium3,4,5. Here we use new geologic and palaeoseismic data to demonstrate that the past six major earthquakes on the SSAF probably occurred during highstands of Lake Cahuilla5,6. To investigate possible causal relationships, we computed time-dependent Coulomb stress changes7,8 due to variations in the lake level. Using a fully coupled model of a poroelastic crust9,10,11overlying a viscoelastic mantle12,13, we find that hydrologic loads increased Coulomb stress on the SSAF by several hundred kilopascals and fault-stressing rates by more than a factor of 2, which is probably sufficient for earthquake triggering7,8. The destabilizing effects of lake inundation are enhanced by a nonvertical fault dip14,15,16,17, the presence of a fault damage zone18,19 and lateral pore-pressure diffusion20,21. Our model may be applicable to other regions in which hydrologic loading, either natural8,22 or anthropogenic1,23, was associated with substantial seismicity.