The optimization study presented herein is aimed to minimize the fuel consumption and engine-out emissions using commercially available EN15940 compatible HVO (Hydrogenated Vegetable Oil) fuel. The investigations were carried out on FEV’s 3rd generation HECS (High Efficiency Combustion System) multi-cylinder engine (1.6L, 4 Cylinder, Euro 6). Using a global DOE approach, the effects of calibration parameters on efficiency and emissions were obtained and analyzed. This was followed by a global optimization procedure to obtain a dedicated calibration for HVO. The study was aiming for efficiency improvement and it was found that at lower loads, higher fractions of low pressure EGR in combination with lower fuel injection pressures were favorable. At higher loads, a combustion center advancement, increase of injection pressure and reduced pilot injection quantities were possible without exceeding the noise and NOx levels of the baseline Diesel.In a second stage, WLTP cycle simulations were used to quantify the emissions and fuel consumption benefits with HVO, both for a drop-in scenario as well as for a scenario where HVO was operated with a dedicated calibration. Simulation results revealed that HVO as drop-in fuel shows overall an improved thermodynamic efficiency. An increased volumetric fuel consumption of ~ 2 % was found due to the lower density of paraffinic HVO fuel. NOx emissions were comparable to baseline Diesel, whereas, a significant reduction in emissions of CO, HC and PM was observed owing to superior ignition behavior, the absence of aromatics or Sulphur and improved evaporation behavior. For the optimized scenario, maintaining NOx and noise targets similar to baseline Diesel, the engine efficiency with HVO improved by 6.3%, corresponding to a tank-to-wheel CO2 reduction of 9%. This efficiency improvement was high enough to compensate the low density of HVO, resulting in an overall improvement in volumetric fuel consumption by 1.6% w.r.t. Diesel. Furthermore, the emissions of HC, CO and PM were reduced by more than 50%. The lower PM emissions with HVO contributes to an extended DPF regeneration interval, thereby reducing DPF related drawbacks.