This article is a systematic review evaluating published clinical evidence of the efficacy of hyperbaric oxygen therapy (HBOT) for wound healing and limb salvage. The data source is the Ovid/Medline database for key word "Hyperbaric Oxygenation" with search limits (human studies, 1978-2008). Results were combined by Boolean AND with 1 of the 3 following searches: (a) wound healing (10 permutations); (b) compromised flap or graft (3); and (c) osteomyelitis (1). The author evaluated 620 citations, of which 64 reported original observational studies and randomized controlled trials (RCTs) on HBOT and healing outcomes. All citations with 5 subjects were selected for full text review (44 articles) and evaluated according to GRADE criteria for high, medium, low, or very low level of evidence. A Cochrane review identified 1 additional study with a low level of evidence. This systematic review discusses and tabulates every article of high or moderate level of evidence. For patients with diabetic foot ulcers (DFU) complicated by surgical infection, HBOT reduces chance of amputation (odds ratio [OR] 0.242, 95% CI: 0.137-0.428) (7 studies) and improves chance of healing (OR 9.992, 95% CI: 3.972-25.132) (6 studies). Positive efficacy corresponds to HBOT-induced hyperoxygenation of at-risk tissue (7 studies) as measured by transcutaneous oximetry. HBOT is associated with remission of about 85% of cases of refractory lower extremity osteomyelitis, but an RCT is lacking to clarify extent of effect. There is a high level of evidence that HBOT reduces risk of amputation in the DFU population by promoting partial and full healing of problem wounds. There is a moderate level of evidence that HBOT promotes healing of arterial ulcers, calciphylactic and refractory vasculitic ulcers, as well as refractory osteomyelitis. There is a low to moderate level of evidence that HBOT promotes successful "take" of compromised flaps and grafts.