Introduction – Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. The arrhythmic substrate is thought to be contributed to by heterogeneously impaired repolarisation, which may be amenable to late Na+ block with ranolazine therapy. Although ranolazine may prevent ectopic triggers, its effects on the arrhythmic substrate are poorly understood. The present study therefore aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods – Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic efficacy. Results – Ranolazine applied to models with VT at baseline prevented VT in 53%, 73% and 80% of models at 3µM, 6µM and 10µM concentrations. Analysis of 70,000 re-entry inducibility protocols showed that efficacy was optimal when applied to models with moderate repolarisation impairment (max JT<370ms equivalent). Ranolazine applied to models with severe-extreme repolarisation impairment increased arrhythmia sustainability. Conclusions – Ranolazine efficacy and safety is critically dependent upon the degree of repolarisation impairment. Ranolazine in cases of moderate basal JT prolongation may reduce refractoriness heterogeneity, preventing conduction blocks and re-entry. Ranolazine in cases of severe-extreme basal JT prolongation can increase arrhythmia sustainability by decreasing refractory periods.