Introduction: Out of hospital cardiac arrest (OHCA) is a time critical and heterogeneous presentation. The most appropriate management strategies remain an issue for debate. The aim of this systematic review and meta-analysis was to determine the association of epinephrine versus placebo with return of spontaneous circulation, survival to hospital admission, survival to hospital discharge and neurological outcomes in out of hospital cardiac arrest. Methods: A systematic review of five databases was performed from inception to August 2018. Only randomised controlled trials were considered eligible for inclusion. The primary outcome was survival to hospital discharge. Secondary outcomes were ROSC, survival to hospital admission, neurological function on discharge and three-month survival. All studies were assessed for level of evidence and risk of bias. Results: Five randomised controlled trials with 17,635 patients were identified for inclusion. Use of epinephrine was associated with increased ROSC (OR = 3.10; 95% CI = 2.16 to 4.45; I2 = 74%; p < 0.0001) and increased survival to hospital admission OR = 2.52; 95% CI = 1.63 to 3.88; I2 = 94%; p < 0.0001). However, epinephrine was not associated with increased survival to discharge (OR = 1.09; 95% CI = 0.48 to 2.47; I2 = 77%; p = 0.84) or differences in neurological outcomes (OR = 0.81; 95% CI = 0.34 to 1.96). Discussion: This study was a systematic review and meta-analysis of epinephrine versus placebo in OHCA. The use of epinephrine was associated with improved ROSC and survival to hospital admission. However, use of epinephrine was not associated with a significant difference in survival to hospital discharge, neurological outcomes or survival to 3 months. Further research is required to control for the confounders during inpatient management.