Flammable materials such as gasoline, ethanol, and diesel fuel are commonly transported in bulk via rail. In many cases, pockets of vapor can be generated inside the tank that can present a hazard if spilled during a collision or other catastrophic accident. Vapor conditions above the Lower Explosive Limit (LEL) if exposed to an external ignition source can result in an explosion or fire. Alternately, residual vapors within a tank present an explosion hazard if not properly vented or inerted prior to maintenance activities. This paper summarizes a generalized study of hazards associated with flammable liquids using computation fluid dynamics (CFD) to predict vapor conditions within a tank or following a spill. The analysis was verified in laboratory testing using scaled tank geometries. A demonstration case was developed using diesel fuel in a locomotive fuel tank. Typical road locomotives carry 3000–5000 gal of diesel fuel during normal operation. As the locomotive consumes fuel, large volumes are available for vapor generation within the tank. In a post-collision scenario, under ambient temperatures over the flash point of the fuel, the vapor that vents to the atmosphere presents a significant fire hazard. Further, flammable mists can be generated by the sprays that develop due to fuel leaks from a moving train. Studies of accident cases over a 10 year period indicated that a fire occurred in 80% of the accidents in which fuel was spilled. A CFD analysis was applied to the geometry associated with a locomotive fuel tank. The analysis models the two phase flow using the “volume of fluid” formalism in Fluent, and using a user defined diesel fuel evaporation algorithm. The tank and environmental parameters included fuel volume, fuel temperature, and air flow within the tank, and critical values of vapor content, temperature and velocity were plotted. The analysis predicted ignition of the external vapor cloud at temperatures relevant to a spill in a summer environment in the southwest, and propagation of the flame into the fuel tank. Laboratory testing confirmed the analysis: Once ignited, a flame propagated into the tank, causing an explosion and fire. The analysis methods developed can be applied to a variety of geometries and fluids, providing a basis for full scale testing. The overall intent of the analysis is to aid in the development of fire mitigation approaches for fuel and flammable material transport that would be practical for railroad use.