The cardiac persistent sodium current (INaP) presents a novel target for cardiac ischaemic protection. Here we investigated the effects of the INaP blocker riluzole in a pig model of regional myocardial ischaemia. Landrace or Large White pigs were subjected to 3 h of ligation of the left anterior descending coronary artery (LAD). Animals received either saline IV (500 ml/hr) throughout the experiment (CONT: n=7) or riluzole IV (2 mg/kg in 2 ml propylene glycol in 100 ml saline) (RIL: n=7) between 15 minutes and 5 minutes prior to ligation. Arrhythmia score was calculated in 5 min epochs. Myocardial damage was assessed using epicardial image analysis and histological sectioning. In CONT, 7/7 animals developed premature ventricular contractions (PVCs), 7/7 developed non‐sustained arrhythmias, 6/7 developed sustained arrhythmias. Of the sustained arrhythmias, 23/28 instances were initiated by R‐on‐T extrasytoles (extrasystoles within the vulnerable period which can trigger re‐entrant arrhythmias). In RIL, 7/7 animals developed PVCs, 6/7 developed non‐sustained arrhythmias, and only 3/7 developed sustained arrhythmias, of which 2/5 instances were R‐on‐T initiated. RIL treated animals showed less myocardial damage compared to CONT (65% smaller surface area (p=0.008) on gross epicardial inspection, 51% less oedema (p=0.01), 53% less fibre waviness (p=0.029) assessed by H&E staining, and 79% fewer fragmented nuclei (p=0.009) assessed by TUNEL. Riluzole significantly reduced Phase 2 (the period associated with irreversible damage) ischaemic R‐on‐T triggered and non‐R‐on‐T arrhythmias and myocardial damage occurring during the 3 h period of regional ischaemia. This article is protected by copyright. All rights reserved.