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Large earthquakes near densely populated areas such as the 1994 Northridge and 1995 Kobe events have caused extensive damage to the physical infrastructure and losses to the regional and national economies. Economic losses are due in part to direct damage and in part to business interruption caused by non-functioning infrastructure and interdependencies among industrial sectors. We developed a regional earthquake loss methodology that emphasizes economic interdependencies at regional and national scales and the mediating role of the transportation network. In an application to the Central U.S. under threat from earthquakes from the New Madrid Seismic Zone, we (1) evaluate regional and national losses from scenario earthquakes, (2) quantify uncertainty on the losses through loss risk curves including contributions from seismicity, attenuation, fragilities, etc. and (3) assess the effectiveness of alternative mitigation strategies. The loss assessment methodology includes spatia