Perineal lesions are a frequent and troublesome complication of Crohn's disease. Although there are various surgical and medical therapeutic regimens available to treat these lesions, all have significant associated morbidity, mortality, and toxicity. Recently, the beneficial effects of hyperbaric oxygen therapy (HBOT) have been described in patients with severe or refractory perineal disease, but the role of HBOT in larger groups or less severely affected patients has not yet been studied, nor has the minimum number of treatments required for initial or complete healing of perineal disease in this population been described. This article reviews the known and theoretical tissue effects of HBOT and discusses its potential role in treating patients with perineal Crohn's disease.