The effect of ultra-high-pressure homogenization (UHPH) on raw whole milk (3.5% fat) was evaluated to obtain processing conditions for the sterilization of milk. Ultra-high-pressure homogenization treatments of 200 and 300 MPa at inlet temperatures (Ti) of 55, 65, 75, and 85°C were compared with a UHT treatment (138°C for 4 s) in terms of microbial inactivation, particle size and microstructure, viscosity, color, buffering capacity, ethanol stability, propensity to proteolysis, and sensory evaluation. The UHPH-treated milks presented a high level of microbial reduction, under the detection limit, for treatments at 300 MPa with Ti of 55, 65, 75, and 85°C, and at 200 MPa with Ti = 85°C, and few survivors in milks treated at 200 MPa with Ti of 55, 65, and 75°C. Furthermore, UHPH treatments performed at 300 MPa with Ti = 75 and 85°C produced sterile milk after sample incubation (30 and 45°C), obtaining similar or better characteristics than UHT milk in color, particle size, viscosity, buffer capacity, ethanol stability, propensity to protein hydrolysis, and lower scores in sensory evaluation for cooked flavor.