We developed a swine model to describe the untreated natural history of severe decompression sickness (DCS) after direct ascent from saturation conditions. In a recompression chamber, neutered male Yorkshire swine were pressurized to a predetermined depth from 50-150 feet of seawater [fsw; 2.52-5.55 atmospheres absolute (ATA)]. After 22 h, they returned to the surface (1 ATA) at 30 fsw/min (0.91 ATA/min) without decompression stops and were observed. Depth was the primary predictor of DCS incidence (R = 0.52, P < 0.0001) and death (R = 0.54, P < 0.0001). Severe DCS, defined as neurological or cardiopulmonary impairment, occurred in 78 of 128 animals, and 42 of 51 animals with cardiopulmonary DCS died within 1 h after surfacing. Within 24 h, 29 of 30 survivors with neurological DCS completely resolved their deficits without intervention. Pretrial Monte Carlo analysis decreased subject requirement without sacrificing power. This model provides a useful platform for investigating the pathophysiology of severe DCS and testing therapeutic interventions. The results raise important questions about present models of human responses to similar decompressive insults.