To improve the personal mobility, safety, and environmental impact of passenger travel and to strengthen regional and national economies, planners, governments, and transportation companies throughout the world have been building high-speed rail (HSR) systems for more than half a century. Although many early systems were principally government projects, public–private partnerships are increasingly being used to design, build, operate, and maintain these HSR networks. However, engaging the private sector requires a clear understanding of the potential profitability of such a system. A key question affecting this understanding is the configuration of the line in terms of its length, number and location of stations, and ultimate alignment. A computer model was developed; it used station, route, and system data to determine the most profitable routes based on the proposed stations. In addition, a sensitivity analysis was conducted to determine which variables had the greatest impact on the costs and returns of an HSR route. The sensitivity analysis led to the division of the design variables into three categories based on their impact on profitability. Variables that were found to have a major influence were project concession period, ridership, fare, annual fare increase, train set availability, cost of building on a viaduct, and land value increase. Categorizing the design variables allows the model to be used more efficiently in a multiphase approach that reduces the time and resources required to assess potential HSR lines.