Oxygen is one of the commonest health-care interventions worldwide. This might suggest that health-care professionals (HCPs) would be knowledgeable and familiar with its uses and limitations. Yet it is apparent, through clinical audit, that oxygen is probably misunderstood by many HCPs. The aim of this critical interpretive synthesis (CIS) is to explore qualitative and quantitative literature in relation to HCPs beliefs and perceptions of oxygen therapy. A systematic search in Medline, Cinahl, Embase, British Nursing Index and PsychInfo using search terms, such as, oxygen therapy, chronic respiratory disease, HCPs and perceptions yielded 1514 studies of which 12 contained data relevant to the review question. Two reviewers independently screened the articles for eligibility against inclusion and exclusion criteria, and data were selected and synthesized with an integrative and interpretive approach using CIS. This allowed diverse empirical evidence to be synthesized to develop existing and new interpretations of data.Three synthetic constructs were interpreted from the available literature, namely, oxygen for symptom relief, levels of knowledge and understanding and oxygen as a therapy for HCPs. The literature alludes to deep-seated beliefs that exist. In order to enhance practice, these beliefs and cultures need to be challenged. Further research is needed to explore HCPs’ perceptions of oxygen therapy in order to inform the seemingly resistant adoption of evidence based practice in relation to oxygen.