AbstractCentral Nervous System Oxygen Toxicity (CNS-OT) is one of the most harmful effects of Enriched Air Nitrox (EAN) diving. Protective factors of the Ketogenic Diet (KD) are antioxidant activity, the prevention of mitochondrial damage and anti-inflammatory mechanisms. We aimed to investigate if a short-term KD may reduce oxidative stress and inflammation during an hyperoxic dive. Samples from six overweight divers (mean ± SD, age: 55.2 ± 4.96 years; BMI: 26.7 ± 0.86 kg/m²) were obtained a) before and after a dive breathing Enriched Air Nitrox and performing 20-minute mild underwater exercise, b) after a dive (same conditions) performed after 7 days of KD. We measured urinary 8-isoprostane and 8-OH-2-deoxyguanosine and plasmatic IL-1β, IL-6 and TNF-α levels. The KD was successful in causing weight loss (3.20 ± 1.31 Kgs, p < 0.01) and in limiting lipid peroxidation (3.63 ± 1.16 vs. 1.11 ± 0.22; p < 0.01) and inflammatory response (IL-1β = 105.7 ± 25.52 vs. 57.03 ± 16.32, p < 0.05; IL-6 = 28.91 ± 4.351 vs. 14.08 ± 1.74, p < 0.001; TNF-α = 78.01 ± 7.69 vs. 64.68 ± 14.56, p < 0.05). A short-term KD seems to be effective in weight loss, in decreasing inflammation and protective towards lipid peroxidation during hyperoxic diving.