A computational fluid dynamics (CFD) study was carried out on a two-stroke uni-flow diesel engine adapted to operate on direct-injected natural gas (NG) with a diesel pilot ignition source. A medium pressure injector was used to inject the natural gas through the cylinder wall slightly above the intake ports during the gas exchange period. The CFD study concentrated on the effect of the injector orientation on the loss of fuel during scavenging and on in-cylinder mixing of the NG fuel. A three-dimensional CFD model of the cylinder configuration was created in order to simulate the scavenging, NG injection and mixing periods during the cycle. A parametric study of the orientation of the NG injector was performed in order to find the optimal design, within manufacturing constraints, which would minimize HC emissions. It was found that the amount of NG fuel lost during the scavenging period could be reduced if the NG injector is directed downward, toward the bowl in the piston. Also, orientating the NG injector tangentially (off the radial line) can reduce the loss of fuel, although to a smaller degree than directing it toward the piston crown. The best configuration, which would require minimal hardware changes, produced over a 50% reduction in fuel loss compared to a baseline configuration.