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Introduction: Several urological conditions that share an impairment of tissue oxygenation can benefit from hyperbaric oxygen therapy; limited evidence is available of its impact on patients undergoing male‐to‐female gender affirmation surgery. Aim: To evaluate the efficacy and safety of hyperbaric oxygen therapy as adjuvant treatment for surgical site infections in patients undergoing male‐to‐female gender affirmation surgery. Methods: This research was conducted as an observational retrospective study. Patients undergoing male‐to‐female gender affirmation surgery at the principal investigators' institution from January 2009 to September 2019, with a discharge diagnosis of complicated superficial or deep wound infections, were included. All patients underwent standard management of wound infection. Subjects received/not‐received hyperbaric oxygen therapy at the surgeon's discretion and were assigned to the hyperbaric oxygen therapy versus non‐hyperbaric oxygen therapy group accordingly. Complete wound healing rate (primary outcome), duration of antibiotic therapy, perineal drain time, bladder catheter time, and hospital stay were recorded. All adverse events that occurred during the study period were described. Results: A total of 156 patients underwent male‐to‐female gender affirmation surgery in the study period. Thirty‐three patients were enrolled. Fifteen subjects belonged to the hyperbaric oxygen therapy group, the other 18 to the non‐hyperbaric oxygen therapy group. No statistically significant differences were found between the two groups at baseline. Penile inversion vaginoplasty and intestinal vaginoplasty were performed in nine (60%) and six (40%) patients of the hyperbaric oxygen therapy group. Only penile inversion vaginoplasty was performed in subjects of the non‐hyperbaric oxygen therapy group. Complete wound healing was obtained in 15 patients (100%) of the hyperbaric oxygen therapy group and 17 patients (94.4%) of the non‐hyperbaric oxygen therapy group (p = 0.35). Duration of antibiotic therapy, perineal drain time, bladder catheter time, and hospital stay were significantly lower in the hyperbaric oxygen therapy group (p < 0.05). Conclusion: Our preliminary data suggest a role of hyperbaric oxygen therapy as adjuvant treatment for surgical site infection in patients undergoing male‐to‐female gender affirmation surgery. Randomized controlled trials properly powered are needed to confirm our findings. [ABSTRACT FROM AUTHOR]