The layered oxide LiNi0.6Mn0.2Co0.2O2 is a very attractive positive electrode material, as shown by good reversible capacity, chemical stability, and cyclability upon long-range cycling in Li-ion batteries and, hopefully, in the near future, in all-solid-state batteries. A large panel of synthesis conditions were explored in order to tailor the size of the primary particles for powders showing structures close to the ideal 2D layered structure (i.e., with less than 3.8% Ni2+ ions in the Li+ sites). Materials with primary particle sizes ranging from 170 nm to 2 μm were obtained. Their electrochemical performance in Li-ion batteries and surface reactivity were characterized in different cycling conditions, as a function of the primary particle size. A significant impact on the performance and reactivity was observed, with obviously better reversible capacity and cyclability for the materials with primary particles ranging between 200 and 400 nm. The analysis of the solid electrolyte interphase formed at the interface between the positive electrode and the electrolyte has shown that larger particles had a larger proportion of lithium salt degradation products, induced by the larger amount of Li2CO3 at their surface. It was also shown that the degradation of the lithium salt was favored at higher cycling rate, whereas that of the organic solvents is a little more favored in larger potential windows with a higher cutoff voltage.