Objective To investigate the effect of rats' injuries and its mechanism caused by specific dose of radiation combined with decompression exposure. Methods 81 male SD rats were randomly divided into control group (n=9), radiation group (n=18), radiation+low-load decompression group (n=18), radiation+medium-load decompression group (n=18), and radiation+high-load decompression group (n=18). In addition to control group, the rats were irradiated with ⁶⁰Co γ rays at 4 Gy and then underwent rapid escape experiments. The high-pressure exposure schemes were to stay underwater 57 m for 30 min, 45 min or 60 min and reduce to normal pressure within (30±5) s, respectively. The high-pressure exposure was not carried out in radiation group. The behavior and death of rats in each group were observed 0.5 h after leaving the cabin. Blood (abdominal aorta) and lung tissues were collected at 3 h and 72 h, respectively. The changes of lung wet-dry weight ratio (W/D), lung pathology and serum levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), intercellular adhesion molecule-1 (ICAM-1) and thromboxane B2 (TXB2) were analyzed. Results Compared with control group and radiation group, radiation+low-load decompression group showed no significant difference in the injury and death rate of rats (P>0.05), while radiation+medium-load decompression group and radiation+high-load decompression group showed significantly increase of the injury and death rate of rats (P<0.05). Compared with control group, other groups showed no significant change in pulmonary W/D at 3 h (P>0.05), and increased at 72 h (P<0.05). HE staining showed that compared with control group, radiation group showed mild lung interstitial edema, while radiation+low-load decompression group showed obvious pulmonary tissue edema and a small number of red blood cells exudated in the alveolar cavity. The edema, congestion and inflammatory cell infiltration of lung tissue were more serious in radiation+medium-load decompression group and radiation+high-load decompression group. Compared with control group and radiation group, all radiation+decompression groups showed an increase in serum levels of IL-1β, IL-6, TNF-α, MDA, NO, ICAM-1 and TXB2 (P<0.05), and a decrease in SOD activity (P<0.05). Compared with radiation+low-load decompression group, radiation+medium-load decompression group and radiation+high-load decompression group showed increase in serum levels of IL-1β, IL-6, MDA, ICAM-1 and TXB2 (P<0.05), and decrease in activity of SOD (P<0.05). Except for control group, serum levels of IL-1β, IL-6, TNF-α, MDA, NO, ICAM-1 and TXB2 were decreased at 72 h compared with 3 h (P<0.05), and SOD activity was increased at 72 h in all groups (P<0.05). Conclusions High-load decompression can increase the injury and death rate of rats exposed to radiation and high pressure. The potential mechanism of the combined injury effect of radiation and decompression was related to inflammation, immune stress, oxidative damage, vasomotor activity and coagulation mechanism.