Noroviruses (NoVs) are the major pathogens causing non-bacterial acute gastroenteritis in the world. To investigate the inactivation effect of high hydrostatic pressure (HHP) on NoVs in oysters under different pressure conditions and the effect of PMAxx in distinguishing infectious NoVs， GⅡ.4 NoVs in oyster digestive gland homogenate and PBS buffer were subjected to HHP treatment with pressure conditions of 200， 300， 400， 500 MPa， respectively， at the initial pressure temperature was 5 ℃ and holding time of 5 min. The normal pressure (0.1 MPa) was used as the control group. After HHP treatment， PMAxx combined with RT-qPCR was applied for the detection of infectious NoVs， transmission electron microscope was used to observe the morphology of NoVs， and then the effect of different pressures on the reduction of GII.4 NoVs was calculated. The effects of HHP treatment on lipids and proteins were evaluated by measuring the malondialdehyde content and protein sulfhydryl content of oysters. The results showed that PMAxx-RT-qPCR could effectively distinguish infectious NoVs. After the HHP treatment of each pressure， NoVs in oyster digestive gland homogenate and PBS buffer showed significant reduction， and the reduction of NoVs in oyster and PBS buffer was >3.49 lg (copies/μL) and >3.61 lg(copies/μL) at the pressure of 500 MPa， respectively， and both of them were reduced below the detection limit； the effect of NoVs in the PBS buffer was better than that of oyster digestive gland homogenate； although the HHP treatment promoted fat oxidation and protein degradation in oysters， the effect on oyster quality was still better than that of heat treatment.