Objectives The current evidence rating for hyperbaric oxygen therapy indications uses the American Heart Association system, which mainly depends on the study design. Study Design and Setting We systematically reviewed the literature and applied the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach to the main patient-important outcomes in each indication. Results We included 17 systematic reviews that synthesized 44 randomized trials and 131 observational studies enrolling 8,145 participants. The quality of evidence for seven indications with category A was high (1), moderate (2), low (2), and very low (2); for 10 indications with category B, it was moderate (1), low (5), and very low (4); and for 1 indication with category C, it was high. The quality of evidence was rated down for the risk of bias and imprecision for most indications and rated up because of large effect size for some indications. Most discrepant ratings were in the indications of decompression illness (C, high), carbon monoxide poisoning (A, very low), and later presentations of idiopathic sudden hearing loss (A, very low). Conclusion The GRADE approach uncovered factors affecting the quality of evidence that were otherwise implicit. Knowing these factors can influence clinicians' confidence in applying hyperbaric oxygen therapy and orient the research agenda. © 2014 Elsevier Inc. All rights reserved.