Many of the major railroad lines in the Mid-America earthquake region are potentially susceptible to high peak ground accelerations (PGA) and soil liquefaction effects due to an earthquake associated with the New Madrid fault. With geographic information systems (GIS) data and analysis techniques, the risk to the rail network posed by a major earthquake in the region was estimated. It was estimated that about 2,107 active rail route miles and 2,082 railroad bridges, including eight major river-crossing bridges over the Ohio and Mississippi Rivers, are in areas with a 2% probability of experiencing PGA values with potential to cause moderate to severe damage (>20% g) in the next 50 years. Because of the importance of this portion of the rail network and the bridges in the region, a model to calculate the cost-effectiveness of retrofitting railway bridges for enhanced seismic resistance was developed. Analysis using the model indicates that retrofitting small to moderately sized bridges is not generally cost-effective in the Mid-America region. However, a sensitivity analysis indicated that for large river-crossing bridges there may be plausible conditions when retrofitting would be cost-effective.