We hypothesised that the protection against oxygen (PAO) of must and wine during vinification by avoiding contact with air can preserve the primary volatile organic compounds (VOCs) of Nerello Mascalese. PAO was performed in two seasons (2020 and 2021) using carbon dioxide pellets (CO2,s) and gas (CO2,g), inactivated yeasts and ascorbic acid during fermentation; the control wine was made via traditional vinification without adding the aforementioned components. During fermentation, the two winemaking processes mainly differed in terms of the application of aeration during maceration/fermentation in the pump-over and délestage activities, and the care taken to avoid contact with oxygen during racking. In both years, higher concentrations of polyphenols and total anthocyanins were found in the PAO wine (about 16 % and 20 % respectively). The concentrations of nerol, citronellol and geraniol were significantly higher in the PAO wine in both seasons, albeit with small differences which affected the sensory evaluation. The free/bound terpenes ratio was 0.35 (PAO) and 0.55 (Control). Bound C13-norisoprenoids contents were higher than the free ones; in the PAO wine, free 3-oxo-α-ionol and bound vomifoliol concentrations were slightly higher than in the control wine. Thiols were measured in Nerello for the first time. In 2020 in particular, sulfanylhexan-1-ol was present in larger amounts in the PAO wine. Applying PAO in the production of Nerello Mascalese modified certain VOCs, as well as the overall free/bound ratio due to the increase in bound VOCs, thus influencing the aroma of the wine.