Hazardous materials traffic originates and terminates at numerous locations throughout the North American railroad network. Rerouting of this traffic, especially toxic inhalation hazard materials, away from populated areas has received considerable attention in recent years as a means of reducing risk. However, rerouting on a route-specific basis is neither simple nor necessarily effective at reducing risk because of physical constraints in the configuration of the rail network and the possible need to increase the miles traveled by hazardous materials so as to avoid populated areas. A more comprehensive approach is rationalization of the transportation route structure for these materials. This does not simply involve trying to reroute traffic between the current set of origins and destinations to avoid population centers en route. Instead, route rationalization encompasses analysis of the entire route structure for a particular material. The objective is to identify opportunities to reduce risk by considering critical factors associated with each possible route, while simultaneously taking into account the production and consumption levels at each location in the network. This paper presents a risk analysis model combined with an optimization technique to formally consider risk reduction by means of rationalization of the hazardous materials transportation rail route structure. The model is flexible and enables optimization of the route structure based on a variety of possible objective functions, including minimization of miles traveled, accident (derailment) probability, likelihood of release, population exposure, and risk.