Three highway bridges spanning the Missouri River flood plain were selected for evaluation of seismic site response for moderate size earthquakes emanating from the New Madrid Seismic Zone (NMSZ) in the Midwestern United States. The NMSZ is known to be capable spawning earthquakes larger than magnitude (M) 7.0, four of which occurred in a three-month period between 1811 and 1812, and the Mw 6.0 earthquake of October 1895 centered near Charleston, Missouri. This study evaluated the likely impacts of long period motion of these historic earthquakes on three long-span highway bridges using geotechnical data obtained from recent investigations. Our results suggest site amplification between 6times and 9times, depending on the magnitude and epicentral distance. We believe that threshold magnitude for serious foundation failure and damage to these bridges is between Mw 6.5 and 6.6. Above these magnitudes widespread liquefaction is predicted, which would effect the peak horizontal acceleration and spectral accelerations, causing the ground motions to be different than predicted. Increase in amplification of the response spectra also should be expected where the periods are higher than 1.0 sec. Therefore, Mw 6.5+ earthquakes at ranges 210-260 km could be expected to engender resonant frequency problems for multiple span bridges and tall buildings (10 to 25 stories) in channel corridors containing 20 to 46 m of unconsolidated sediment.