The effect of hyperbaric oxygen (HBO) as an immunosuppressive agent was evaluated by using a highly immunogenic skin allograft mouse model. Immune-histoincompatible female C57BL/6 and BALB/c mice (N = 30) were randomly assigned to three groups receiving no treatment (control group), low dose HBO treatment (two treatments once a week), and intermediate HBO treatment (two treatments 3 times/wk) 1 wk before and 2 wk after transplantation of a 1.5 x 2 cm full thickness skin allograft from the back. Rejection was observed a Day 7 and was completed 14 days after surgery in controls. Low dose and intermediate HBO treatment delayed skin allograft rejection, which was histologically confirmed.