Introduction: Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) may experience life-threatening arrhythmic events (LAE) despite standard-of-care treatment with beta-blockers (BB), but risk stratification is not well defined.Hypothesis: Both clinical and genetic risk factors predispose to BB failure, including the class of BBs (β1-selective vs. non-selective).Methods: LAE was defined as the composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia. We fitted a Cox proportional hazards regression model with multiple events during BB treatment only with the following explanatory covariates: 1) LAE before diagnosis, 2) unexplained syncope before diagnosis, 3) genotype, and 4) type of BB (as time-dependent variable).Results: We included n=238 CPVT patients: n=135 (57%) probands, n=134 (56%) females, n=216 (91%) RYR2, n=10 (4%) CASQ2, n=5 (2%) RYR2-Loss-of-Function, n=4 (2%) TRDN and n=3 (1%) TECRL. Before the diagnosis, 48/238 (20%) patients experienced an LAE, while 110/238 (46%) patients experienced an unexplained syncope. During a mean follow-up of 9.7±7.6 years of treatment with BB only, 35/238 (15%) patients experienced one or more LAEs (annual rate 4.0%, 95% CI: 3.1%-5.0%), with a mean of 2.1±2.4 LAEs per patient. Multivariable analysis with multiple events at follow-up showed that LAE before diagnosis (HR 3.9; 95%CI: 2.3-6.8; p<0.001), syncope before diagnosis (HR 2.7; 95%CI: 1.5-5.0; p=0.001), TRDN mutations (HR 10.9; 95%CI: 4.2-28.0; p<0.001) and use of β1-selective BBs (HR 3.0; 95%CI: 1.7-5.3; p<0.001) were significantly associated with the occurrence of LAE (Figure).Conclusions: In patients with CPVT, history of LAE and/or unexplained syncope before diagnosis, TRDN mutations and the use of selective BBs are independent risk factors for the occurrence of multiple LAEs at follow-up during BB treatment.