The average seismogenic thickness, measured from the surface down to maximum depth of earthquake rupture, for the southern California crust is 15.0 km (+1.2/–1.1 km). We determine the seismogenic thickness using the depth distribution of the seismic moment release of ∼19 years of seismicity. We calibrate the depth distribution of moment release from background seismicity by comparing the maximum depth of rupture during moderate- to large-magnitude earthquakes to the premainshock background seismicity of the respective mainshock region. The calibration shows that the depth above which 99.9% of the moment release of background seismicity occurs reliably estimates the maximum depth of rupture during moderate to large earthquakes. Locally, the seismogenic thickness is highly variable, ranging from less than 10 km in the Salton Trough to greater than 25 km at the southwestern edge of the San Joaquin Valley. Similarly, the seismogenic thickness along the major strike-slip faults can vary significantly along strike. Changes in seismogenic thickness along strike do not correspond to the mapped surface segmentation of the major southern California strike-slip fault systems. In the future, such estimates of the seismogenic thickness can be used to refine existing seismic-hazard estimates for southern California.