Novel inactivation methods are needed to control the spread of foodborne viruses responsible for nonbacterial gastroenteritis worldwide. The advent of high-pressure homogenization combining high pressure, shear stress, and cavitation provides the opportunity to evaluate this technology for viral inactivation in fluid foods under continuous processing conditions. Our objective was to evaluate murine norovirus (MNV-1) and MS2 coliphage (single-stranded RNA) as human enteric virus surrogates for their susceptibility to a novel high-pressure homogenization process for application in commercial settings. Experiments were conducted in duplicate with MNV-1 and MS2 coliphage in phosphate-buffered saline, using homogenization pressures of 0, 100, 200, 250, and 300 MPa (the maximum achievable by the homogenizer), resulting in exposure temperatures of 24, 46, 63, 70, and 75 degrees C, respectively, for <2 s. Only homogenization pressures of 300 MPa at 75 degrees C showed inactivation of approximately 3 log PFU for MS2 from an initial approximately 6 log PFU. Also, MNV-1 showed inactivation of approximately 0.8 log PFU at 300 MPa. Further studies are warranted to validate this inactivation process, which can retain the sensory and nutritional value of fluid food and shows promise for application in industrial environments.