Objectives: This study sought to reveal the characteristics and radiofrequency catheter ablation (RFCA) outcomes of multifocal His-Purkinje system (HPS) ventricular arrhythmias (VAs). Background: The details of those VAs, especially the safety and efficacy of their RFCA treatment, remain unclear. Methods: Thirty consecutive patients who underwent RFCA of focal HPS VAs between 2010 and 2016 (unifocal = 24, multifocal = 6) were studied by measuring the electrophysiological variables within the HPS. Results: Multifocal premature ventricular contractions (n = 1) and ventricular fibrillation (VF) (n = 5) were identified in the left posterior (n = 6), anterior (n = 4), and septal fascicles (n = 1), as well as the basal left bundle branch (LBB) (n = 2) and right bundle branch (RBB) (n = 2). In 2 patients with unifocal VAs and 4 patients with multifocal VAs, preferential conduction from an origin within the proximal fascicle (n = 4) or LBB (n = 2) to ≤3 breakout sites in the distal fascicles occurred with split or fractionated Purkinje potentials and/or conduction block at the site of origin. Among the multifocal VAs, 11 fascicle VAs, 1 RBB VA, and 1 LBB VA were successfully ablated with fascicular and/or bundle branch block, and complete atrioventricular block (CAVB), respectively. In the remaining LBB VAs and RBB VAs, RFCA was abandoned to avoid CAVB. Recurrence of ablated VAs or the incidence of VF did not differ between the unifocal and multifocal HPS VAs. Freedom from any HPS VA after RFCA was significantly higher in the patients with unifocal VAs than in the patients with multifocal VAs (92% vs. 33%; p = 0.001). Conclusions: Multifocal HPS VAs could occur and often present with preferential conduction from proximal origins to distal breakout sites within the HPS with abnormal Purkinje potentials and/or conduction properties. RFCA was effective but was limited by the risk of HPS impairment.