Purpose <p>Home oxygen therapy (HOT) is administered to patients with impaired pulmonary function who cannot adequately oxygenate themselves to meet systemic metabolic demands. Although regional anesthesia (RA) is beneficial for patients requiring HOT, comparative evidence between regional and general anesthesia (GA) is lacking. Thus, this study aimed to compare postoperative outcomes between RA and GA in patients requiring HOT.</p> Methods <p>We collected data from a nationwide hospital-based database spanning from April 2014 to June 2022. We included patients who received HOT before limb or lower abdominal surgery and divided them into those who received GA and those who received RA. The primary outcome was 30-day hospital-free days. Secondary outcomes included 30-day mortality, postoperative pulmonary complications, and non-pulmonary complications. Additionally, we calculated the propensity scores and applied the overlap weighting method. Unmeasured confounders were addressed using high-dimensional propensity scores.</p> Results <p>Among 1064 included surgeries, 565 and 499 were assigned to the GA and RA groups, respectively. Post-adjustment, no significant difference in hospital-free days was observed between the GA (10.46&#xa0;days) and RA (11.29&#xa0;days) groups (hospital-free day difference: 0.83; 95% confidence interval: − 0.56 to 2.23; <i>p</i> = 0.24). No significant between-group differences were observed in secondary outcomes, including 30-day mortality (odds ratio = 0.97; 95% confidence interval: 0.61–1.56; <i>p</i> = 0.67) and postoperative pulmonary complications (OR = 1.00; 95% CI 0.68–1.48; <i>p</i> = 0.99). Additionally, no difference was noted between the main analysis and the high-dimensional propensity score results for primary and secondary outcomes.</p> Conclusions <p>Our findings suggest no association between the anesthesia method used and the 30-day hospital-free days among patients requiring HOT.</p>