Background: Out-of-hospital cardiac arrest (OHCA) remains a critical public health challenge, with survival rates influenced by regional emergency medical services (EMS) protocols. This study evaluates the impact of EMS-administered medications on return of spontaneous circulation (ROSC) in OHCA cases within the Lublin Voivodeship, Poland. Methods: A retrospective analysis of 4361 OHCA cases from 2014 to 2017 was conducted using EMS records identified through International Classification of Diseases, Tenth Revision (ICD-10) and ICD-9 codes. Statistical analyses, including chi-square tests and multivariate logistic regression, assessed the associations between medication administration and ROSC outcomes. Results: ROSC was achieved in 32.7% of cases. Epinephrine, administered in 89.06% of cases, was not significantly associated with ROSC (p = 0.425). Amiodarone, used in 18.27% of cases, was significantly associated with ROSC in shockable rhythms (p = 0.012). Sodium bicarbonate, given in 23.12%of cases, was linked to ROSC in overdose-related arrests (p = 0.034) but showed lower effectiveness outside of such cases. Dopamine, administered in 22.51% of cases, was positively correlated with ROSC (p = 0.018), as was fluid therapy, provided in 62.67%of cases (p = 0.021). Medication administration varied by incident location and etiology, with amiodarone and sodium bicarbonate more frequently used in workplace incidents, and sodium bicarbonate and fluid therapy more common in overdose-related OHCA cases. Amiodarone use was significantly higher in ventricular fibrillation/ventricular tachycardia (VF/VT) cases (p = 0.013). Conclusions: This regional study underscores the critical role of EMS-administered medications and contextual factors in OHCA outcomes. Findings suggest that targeted medication use based on initial heart rhythm and arrest etiology may enhance resuscitation success. Future multicenter or prospective studies are needed to validate these results and inform global prehospital resuscitation strategie. Keywords: Out-of-hospital cardiac arrest; Emergency medical services; Epinephrine; Amiodarone; Return of spontaneous circulation