The use of epinephrine is currently recommended as a treatment option for patients with cardiac arrest. The primary objective of this systematic review was to determine if epinephrine use during cardiac arrest is associated with improved survival to hospital discharge. MEDLINE, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, International Pharmaceutical Abstracts, and Biological Abstracts (BIOSIS Previews), and bibliographies of previous systematic reviews. Studies involving patients with cardiac arrest that compared epinephrine to no epinephrine (or placebo) with regard to survival to hospital discharge or 30-day survival. Randomized controlled trials (RCTs) and observational studies were included. The results were stratified into three groups: 1) RCTs, 2) observational studies with unadjusted data (observational-U), and 3) observational studies with adjusted data using multivariate analysis (observational-A). There were a total of 10 studies included in the systematic review and nine studies were included in the meta-analysis. The association between epinephrine use and survival to hospital discharge, grouped by study type was not significant for RCTs (OR 2.33, 95% CI 0.85 to 6.40; p=0.10; I2=0.00%) or observational-U studies (OR 1.17, 95% CI 0.67 to 2.07; p=0.58; I2=76.68%). But epinephrine was associated with decreased survival in observational-A studies (OR 0.43, 95% CI 0.40 to 0.48; P<0.01; I2=0.00%). Epinephrine use during cardiac arrest is not associated with improved survival to hospital discharge. Observational studies with a lower-risk for bias suggest that it may be associated with decreased survival.