Current studies of fault interaction lack sufficiently long earthquake records and measurements of fault slip-rates over multiple seismic cycles to fully investigate the effects of interseismic loading and co-seismic stress changes on the surrounding fault network. We model elastic interactions between 97 faults from 30 earthquakes since 1349 AD in central Italy to investigate the relative importance of co-seismic stress changes versus interseismic stress accumulation for earthquake occurrence and fault interaction. This region has an exceptionally long, 667-year record of historical earthquakes and detailed constraints on the locations and slip-rates of its active normal faults. Of 21 earthquakes since 1654, 20 events occurred on faults where combined co-seismic and interseismic loading stresses were positive even though ~20% of all faults are in ‘stress shadows’ at any one time. Furthermore, the Coulomb stress on the faults that experience earthquakes is statistically different from a random sequence of earthquakes in the region. We show how co-seismic Coulomb stress changes can alter earthquake inter-event times by c.103 years, and fault length controls the intensity of this effect. Static Coulomb stress changes cause greater inter-event perturbations on shorter faults in areas characterized by lower strain (or slip) rates. The exceptional duration and number of earthquakes we model enable us to demonstrate the importance of combining long earthquake records with detailed knowledge of fault geometries, slip-rates and kinematics to understand the impact of stress changes in complex networks of active faults.