Background <p>The comparative effectiveness of different hyperbaric oxygen (HBO) therapy doses in the acute treatment of central retinal artery occlusion (CRAO) has not been evaluated.</p> Methods <p>This retrospective cohort study aimed to compare the efficacy of an initial 2.8_ATA HBO session (HBO18) to the more prevalent 2.0_ATA protocol (HBO10). Excluded were patients with suspected inflammatory arteritis or branch retinal artery occlusion, and when HBO was medically contraindicated. Following the initial session, all patients completed two additional HBO10 sessions within 24 h. The primary outcome was the change in best corrected visual acuity (ΔBCVA) within 24 ± 4 h. Safety outcomes included neurological events suggestive of central oxygen toxicity and barotrauma-related symptoms.</p> Results <p>Improvement in ΔBCVA was significantly greater in the HBO18 group (median 0.62 LogMAR, mean −0.81 ± 0.73) compared with the HBO10 group (median 0.22 LogMAR, mean −0.34 ± 0.40, <i>p</i> &lt; 0.001). Adverse events were similar in incidence between the treatment groups, with no severe occurrences necessitating the discontinuation of HBO reported. In multivariate analysis, HBO18 use was associated with a 0.5 LogMAR improvement in BCVA at 24 h (95% CI 0.3–0.7, <i>p</i> &lt; 0.001), with greater initial BCVA impairment and shorter time to HBO further associated with better outcomes (0.20 LogMAR, 95% CI 0.08–0.31, <i>p</i> = 0.001; and 0.04 LogMAR/hour, 95% CI 0.02–0.04, <i>p</i> = 0.01, respectively).</p> Conclusions <p>HBO18 as the initial therapy for CRAO seems to be associated with better short-term improvement in BCVA, compared with HBO10.</p>