Two-Stroke (2S) Compression Ignition (CI) engines have been used in aviation since World War II, for their excellent fuel efficiency and lightweight construction. In a modern light aircraft, these advantages still remain, along with the capability to run on jet fuel instead of gasoline. However, the design of these engines must be deeply revised, in order to incorporate the recent technologies, and it must be optimized with the support of CAE tools. The paper presents a CFD optimization of a turbocharged 2S CI 5.6 L flat-six aircraft engine developed by CMD. The scavenging system is of the Uniflow type, with exhaust poppet valves and a set of piston-controlled ports along the cylinder liner. Two mechanical superchargers are serially connected to the turbochargers. The crankshaft can be directly coupled to the propeller, thanks to its excellent balance and the relatively low maximum engine speed (2600 rpm). Differently from previous papers published on the same engine, the current study is focused on two crucial design topics: the optimization of the supercharging system and of the injection strategy. A customized version of KIVA-3V is used for the 3D-CFD cylinder analyses, while a commercial 1D-CFD code is employed to model the whole engine. The study is supported by a comprehensive experimental campaign, that permitted the accurate calibration of the numerical models. In comparison to any Four-Stroke delivering the same maximum power (400 HP at 2600 rpm, sea level), the analyzed engine is very light (about 220 kg), and efficient (211 g/kWh at typical cruise conditions). Despite the high performance, peak cylinder pressure and turbine inlet temperature at sea level are relatively low: 125 bar, 850 K. At rated power (360 HP@2400 rpm, sea level) combustion is complete and smoke-less, thanks to the optimization of the injection strategy, supported by the previous CFD analysis. The engine can operate at altitudes as high as 5500 m (18,000 feet), still delivering 270 HP at 2400 rpm, without relevant reduction of fuel efficiency. The key for the performance at high altitudes is the choice of the turbocharger considering the compressor choke limit easly reachable at high altitudes.