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Ultra-High Pressure Homogenization (UHPH) is an emerging, efficient and fast technology that can be applied at different stages in winemaking in order to reduce or avoid the use of sulphites or other antimicrobial and antioxidant treatments. During 2022 vintage, four batches of must of three different white cultivars (Vitis vinifera L.) were processed by UHPH at 300 MPa with an inlet temperature (Ti) of 4 ºC and their effectiveness was compared with control batches (without SO2 addition) and musts that were sulphited with 60 mg/L of total SO2. A complete inactivation of yeasts and bacteria was achieved when grape juices were processed by UHPH, reaching up to 7 log of reduction in yeasts, 4.6 log for acetic acid bacteria and 4.3 log for lactic acid bacteria. All UHPH musts remained stable from a microbiological point of view for more than 8 months stored at 4 ºC in aseptic containers. Results showed that when antioxidant activity, colour intensity and total phenol index were measured, UHPH can be considered a protective technique, with a similar action to that of adding SO2. Furthermore, PPO enzymatic activity was completely inactivated in UHPH and sulphited musts. When a red wine contaminated by Brettanomyces was treated by UHPH at 300 MPa and Ti = 17 ºC, a 6.6 log reduction was obtained for this spoilage microorganism and no increase of volatile phenols were detected after 2 months.