The paper reports and discusses the results of electrochemical tests carried out according to the DOE Battery Test Manual for plug-in Hybrid Electric Vehicles (PHEVs) on laboratory high-voltage graphite/LiNi0.4Mn1.6O4 cells with electrode formulation and mass-loading suitable for scale-up, and mixed ethylene carbonate–dimethyl carbonate with two diverse lithium salts, lithium tris(pentafluoroethyl)trifluorophosphate and LiPF6, as electrolytes. The cells, assembled with two different separators, a polypropylene monolayer separator (Celgard®2400) and a reinforced polyvinylidene fluoride macroporous membrane (PVdF-NCC), were also tested by deep charge/discharge cycles. The results show the strong impact of the separator on high-rate cell functioning in PHEVs.