The present optimization study is aimed to minimize the fuel consumption and engine emissions using a commercially available EN15940 compatible HVO (Hydrogenated Vegetable Oil) fuel. The Investigations were carried 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 where obtained and analyzed, followed by a global DOE optimization procedure to obtain a dedicated calibration for HVO. Aiming for efficiency improvement, it was found that at lower loads higher fractions of low pressure EGR (LP EGR) in combination with lower fuel injection pressures were favorable. At higher loads, an increase of injection pressure along with lower pilot injection quantities was possible without exceeding the noise and NOx levels of the baseline Diesel. In a second stage, WLTP cycle simulations where used to quantify the emission 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. WLTP cycle results revealed that for HVO as drop-in fuel, even with an improved thermodynamic efficiency, the volumetric fuel consumption increased by ~ 2.2%, mainly due to 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 due to superior ignition behavior, absence of aromatics & sulphur and improved evaporation behavior. For the optimized scenario, at 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. optimized Diesel calibration. Furthermore, the emissions of HC, CO and PM where reduced in the range of ~ 30 to 70%. The lower PM emissions with HVO could further contribute to an extended DPF regeneration interval, and thereby, reducing the energy demand for DPF regeneration.