Epinephrine plays an important role in cardiopulmonary resuscitation (CPR) and is recommended to be administered at 1 mg every 3 to 5 minutes. However, there have been few studies comparing the outcomes between 3 and 4 minutes. In this study, we compared the prognosis between administration of epinephrine at intervals of 3 and 4 minutes in out-of-hospital cardiac arrest (OHCA). If there is no difference in prognosis between the two groups, we can suggest it is efficient to administer epinephrine at intervals of 4 minutes, which is two cycles of advanced cardiac life support (ACLS), considering the ACLS cycle is 2 minutes. We conducted a retrospective study on patients aged 18 years and above admitted for non-traumatic OHCA at Ulsan University Hospital’s Emergency Department between May 2021 and October 2023. Patients were categorized based on epinephrine administration intervals of every 3 or 4 minutes during in-hospital CPR. Primary outcomes assessed were return of spontaneous circulation (ROSC) rate, survival until intensive care unit (ICU) admission, and cerebral performance categories (CPC) at hospital discharge. Additional analyses included total CPR time and epinephrine dose used. Propensity score matching was employed to mitigate baseline characteristic differences between the two groups. Results revealed no significant differences in ROSC rates, survival until ICU admission, or CPC scale scores at discharge between the 3- and 4-minute interval groups. The study suggests that extending the interval of epinephrine administration to 4 minutes does not compromise patient outcomes compared to the conventional 3-minute interval. This study underscores the potential for optimizing CPR protocols to improve patient care and resource utilization.