In recent years, several bridge failures have been observed around the world. These bridge failures are partially due to the lack of financial resources that forces owners to keep bridges in service under undesired circumstances. Given the importance that fatigue and overloading have been playing on bridge failures, the objective of this paper is to present an approach to assess the probability of failure of continuous highway steel bridge superstructures under the combined effect of fatigue damage and overloading. This objective is achieved by performing Monte Carlo simulations on a representative sample of medium length I-girder bridge configurations based on statistical data collected in North America. Damage location, permanent loads, truck gross weight, and axle configurations were assumed to be random variables. The probability of overloading events was modeled as a Poisson’s process. Accordingly, the probability of overloading events was found close to 10% on bridges with high traffic volume after being in service for about 100 years.