A KIVA-based CFD tool has been utilized to simulate the effect of a Common-Rail injection system applied to a large, uniflow-scavenged, two-stroke diesel engine. In particular, predictions for variations of injection pressure and injection duration have been validated with experimental data. The computational models have been evaluated according to their predictive capabilities of the combustion behavior reflected by the pressure and heat release rate history and the effects on nitric oxide formation and wall temperature trends.In general, the predicted trends are in good agreement with the experimental observations, thus demonstrating the potential of CFD as a design tool for the development of large diesel engines equipped with Common-Rail injection. Existing deficiencies are identified and can be explained in terms of model limitations, specifically with respect to the description of turbulence and combustion chemistry. Approaches appropriate to overcome the present limitations and further improve the predictive capabilities are proposed.