Objective: To investigate variations in the effects of prehospital advanced airway management (AAM) on outcomes of out-of-hospital cardiac arrest (OHCA) patients according to regional emergency medical service (EMS) systems in four Asian cities. Methods: We enrolled adult patients with EMS-treated OHCA of presumed cardiac origin between 2012 and 2014 from Osaka (Japan), Seoul (Republic of Korea), Singapore (Singapore), and Taipei (Taiwan). The main exposure variable was prehospital AAM. The primary endpoint was neurological recovery. We compared outcomes between the prehospital AAM and non-AAM groups using multivariable logistic regression with an interaction term between prehospital AAM and the four Asian cities. Results: A total of 16,510 patients were included in the final analyses. The rates of prehospital AAM varied among Osaka, Seoul, Singapore, and Taipei (65.0%, 19.2%, 84.9%, and 34.1%, respectively). The non-AAM group showed better outcomes than the AAM group (adjusted odds ratio [aOR] for neurological recovery 0.30; 95% confidence interval [CI], 0.24–0.38]). In the interaction model for neurological recovery, the aORs for AAM in Osaka and Singapore were 0.12 (95% CI, 0.06–0.26) and 0.21 (95% CI, 0.16–0.28), respectively. In Seoul and Taipei, the association between prehospital AAM and neurological recovery was not significant (aOR 0.58 [95% CI, 0.31–1.10] and 0.79 [95% CI, 0.52–1.20], respectively). The interaction between prehospital AAM and region was significant (P=0.01). Conclusion The effects of prehospital AAM on outcomes of OHCA patients differed according to regional variability in the EMS systems.