Hyperbaric oxygen therapy (HBOT) involves the risk of central nervous system oxygen toxicity (CNS-OT), including seizures in patients breathing oxygen at pressures ≥ 2 atmospheres absolute. This study aimed to determine the seizure frequency and assess the clinical benefit of a 5-minute air-break (5´-AIRBK).Twenty-year (1999-2018) retrospective analysis of all consecutive treatments with HBOT. Medical records were reviewed to determine patient demographics, comorbidities, HBOT indications, and seizure characteristics and timing. Seizure frequency was compared before and after incorporating a 5´-AIRBK in the treatment protocol. Chi-square testing was performed using SPSS (version 24.0); P < 0.05 was accepted as statistically significant.We evaluated 188,335 HBOT sessions (74,255 before versus 114,080 after introducing a 5´-AIRBK). A total of 43 seizures were observed: 29 before and 14 after the 5´-AIRBK introduction (3.9 versus 1.2 per 10,000 treatments; P < 0.0001). Seizures occurred after a median of 57 (range 15-85) minutes following compression and after a median of 21 HBOT sessions (1-126). Patients experiencing seizures were undergoing treatment for: diabetic ulcer (n = 11); acute traumatic peripheral ischaemia (ATPI) (n = 6); non-diabetic ulcer (n = 5); sudden sensorineural hearing loss (n = 5); chronic refractory osteomyelitis (n = 5); radionecrosis (n = 3); necrotising fasciitis (NF) (n = 2); and haemorrhagic cystitis after allogeneic bone marrow transplantation (n = 1). ATPI and NF had a considerably higher relative frequency of seizures compared to other indications.A statistically significant lower seizure frequency was achieved with a 5´-AIRBK. Assessing and defining the appropriate patient/treatment profile can be useful to minimise the risk of CNS-OT.