Background: Disabled submarine (DISSUB) survivors will achieve inert gas tissue saturation within 24 h. Direct ascent to the surface when saturated carries a high risk of decompression sickness (DCS) and death, yet may be necessary during rescue or escape. Oxygen has demonstrated benefits in decreasing morbidity and mortality resulting from DCS by enhancing inert gas elimination. Perfluorocarbons (PFCs) also mitigate the effects of DCS by decreasing bubble formation and increasing O₂ delivery. Hypothesis: Combining O₂ pre-breathe (OPB) and PFC administration will reduce the incidence of DCS and death following saturation in an established 20-kg swine model. Methods: Yorkshire swine (20 ± 6.5 kg) were compressed to 5 ATA in a dry chamber for 22 h before randomization into 1 of 4 groups: 1) air and saline, 2) OPB and saline, 3) OPB with PFC given at depth, 4) OPB with PFC given after surfacing. OPB animals received >90% O₂ for 9 min at depth. All animals were returned to the surface (1 ATA) without decompression stops. Results: The incidence of severe DCS < 2 h after surfacing at 96%, 63%, 82% and 29% for groups 1, 2, 3 and 4, respectively. The incidence of death was 88%, 41%, 54%, and 5%, for groups 1, 2, 3 and 4, respectively. Conclusions: OPB combined with PFC administration after surfacing provided the greatest reduction in DCS morbidity and mortality in a saturation swine model. O₂-related seizure activity before reaching surface did not negatively affect outcome, but further safety studies are warranted.