Background. The benefit of prehospital epinephrine in out-of-hospital cardiac arrest (OHCA) was shown in a recent large placebo-controlled trial. However, placebo-controlled studies cannot identify the nonpharmacologic influences on concurrent or downstream events that might modify the main effect positively or negatively. We sought to identify the real-world effect of epinephrine from a clinical registry using Bayesian network with time-sequence constraints. Methods. We analyzed a prospective regional registry of OHCA where a prehospital advanced life support (ALS) protocol named “Smart ALS (SALS)” was gradually implemented from July 2015 to December 2016. Using Bayesian network, a causal structure was estimated. The effect of epinephrine and SALS program was modelled based on the structure using extended Cox-regression and logistic regression, respectively. Results. Among 4324 patients, SALS was applied to 2351 (54.4%) and epinephrine was administered in 1644 (38.0%). Epinephrine was associated with faster ROSC rate in nonshockable rhythm (HR: 2.02, 6.94, and 7.43; 95% CI: 1.08–3.78, 4.15–11.61, and 2.92–18.91, respectively, for 1–10, 11–20, and >20 minutes) while it was associated with slower rate up to 20 minutes in shockable rhythm (HR: 0.40, 0.50, and 2.20; 95% CI: 0.21–0.76, 0.32–0.77, and 0.76–6.33). SALS was associated with increased prehospital ROSC and neurologic recovery in noncardiac etiology (HR: 5.36 and 2.05; 95% CI: 3.48–8.24 and 1.40–3.01, respectively, for nonshockable and shockable rhythm). Conclusions. Epinephrine was associated with faster ROSC rate in nonshockable rhythm but slower rate in shockable rhythm up to 20 minutes. SALS was associated with improved prehospital ROSC and neurologic recovery in noncardiac etiology.