In an effort to better understand the effects of hyperbaric oxygen therapy on ischemic tissue, we monitored the real-time changes in subcutaneous tissue oxygen tension before, during, and after exposure to hyperbaric oxygen treatments. We identified an elevation of the tissue oxygen partial pressure to over 300 mmHg during the treatment period (up from a baseline mean of 24 mmHg) in a sustained ischemia rabbit ear model (n = 22 rabbits). There was no sustained change in tissue oxygen tension beyond the period of treatment. This manner of response is consistent with several current theories used to explain the mechanism of action of hyperbaric oxygen therapy. It is also consonant with our opinion that molecular oxygen, when delivered at high pressure, can function both as a respiratory metabolite and as a signal transducer. We also studied the impact of nontherapeutic 100% oxygen at 1 atm on tissue. The sustained peak tissue oxygen tension during such challenges increased in direct proportion to the number of hyperbaric oxygen treatments given. The clinical relevance and extension of these findings are discussed.