The recent interest in alternative non-fossil fuels has led researchers to evaluate several alcohol-based formulations. However, one of the main requirements for innovative fuels is to be compatible with existing units’ hardware, so that full replacement or smart flexible-fuel strategies can be smoothly adopted.n-Butanol is considered as a promising candidate to replace commercial gasoline, given its ease of production from bio-mass and its main physical and chemical properties similar to those of Gasoline.The compared behavior of n-butanol and gasoline was analyzed in an optically-accessible DISI engine in a previous paper . CFD simulations explained the main outcomes of the experimental campaign in terms of combustion behavior for two operating conditions. In particular, the first-order role of the slower evaporation rate of n-butanol compared to gasoline was highlighted when the two fuels were operated under the same injection phasing. The poor n-butanol/air mixture homogeneity was found to be a major limiting factor on the potential benefit of the use of n-butanol.This outcome is further deepened in this paper by numerically exploring different mixture preparation strategies for n-butanol. To this aim, variations of the injection phasing and profile are analyzed, including the use of multiple injection strategies. An optimized fuel injection strategy is then numerically identified considering mixture homogeneity, engine torque output and tailpipe emissions of soot and NOx. In order to confirm the validity of the CFD approach, this strategy is experimentally tested to finally draw conclusions on the potential of n-butanol in modern GDI units.