Deep sea divers, aviators and astronauts are at risk of decompression sickness when the ambient pressure reductions exceed a critical threshold. Venous bubbles associated with decompression sickness have the potential to react with the vascular membrane and adjacent blood products, eliciting an inflammatory cascade. Preventive measures usually involve careful decompression procedures to avoid or reduce bubble formation. De-nitrogenation with 100% oxygen pre-breathing as a preventive measure has been well established at least in altitude decompression exposures. The objective of this study was to determine the physiological and biochemical effects of Hyperbaric Oxygen Pre-breathe (HBOP) upon decompression from a hyperbaric exposure. Male Sprague-Dawley rats were randomly assigned to one of eight groups. Two experimental groups received HBOP at 1 and 18 hours prior to decompression, as compared with ground level oxygen or non-treated groups that still experienced decompression stress, and the associated non-decompressed controls. The results showed decreased extravascular lung water (pulmonary edema), bronchoalveolar lavage and pleural protein and arterial, broncho-alveolar lavage, and urine leukotriene E4 (LKE4) levels in both the 1Hr and 18Hr HBOP decompressed rats compared to non-oxygenated decompressed rats, as well as a decreased overall expression of signs of decompression sickness. This study indicates that HBOP-treated rats exhibit fewer signs and complications of decompression sickness compared with non-treated or ground level oxygen treated rats.