Despite numerous studies, controversies about the best intraoperative FiO₂ remain. In 2016, the World Health Organization (WHO) recommended that adult patients undergoing general anaesthesia should be ventilated intraoperatively with an 80% FiO₂ to reduce surgical site infection (SSI). However, several data suggest that hyperoxia could have adverse effects. In order to determine the potential effect of FiO₂ on SSI, we included in this systematic review 23 studies (among which 21 randomised controlled trials [RCT]) published between 1999 and 2020, comparing intraoperative high versus low FiO₂. Results were heterogeneous but most recent studies on one hand, and the largest RCTs on the other hand, reported no difference on the incidence of SSI regarding intraoperative FiO₂ during general anaesthesia. There was also no difference in the incidence of SSI depending of intraoperative FiO₂ in patients receiving regional anaesthesia. The review on secondary endpoints (respiratory and cardiovascular adverse events, postoperative nausea and vomiting, postoperative length-of-stay and mortality) also failed to support the use of high FiO₂. On the opposite, some data from follow-up analyses and registry studies suggested a possible negative effect of high intraoperative FiO₂ on long-term outcomes. In conclusion, the systematic administration of a high intraoperative FiO₂ in order to decrease SSI or improve other perioperative outcomes seems unjustified in the light of the evidence currently available in the literature.