Flecainide, a class Ic anti-arrhythmic, has emerged as an effective therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT) 1; a malignant arrhythmia characterized by dysfunctional sarcoplasmic reticulum (SR) Ca2+ release 2. It has been proposed that the clinical efficacy of flecainide in CPVT is due to the combined actions of direct blockade of cardiac ryanodine receptors (RyR2) and Na+ channel inhibition 3. However, there is presently no direct evidence to support the notion that flecainide blocks RyR2 Ca2+ flux in the physiologically relevant (luminal to cytoplasmic) direction. In this study, we examined in detail the effect of flecainide on the human RyR2 channel to establish whether direct blockade of physiologically relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT. We have investigated the interactions of flecainide with individual recombinant RyR2 channels reconstituted into planar phospholipid bilayers under voltage clamp conditions. Data are given as mean±SEM, compared using t-tests. Consistent with earlier reports 1,3, we show that flecainide blocked cation movement through the channel in the non-physiological direction. The probability of block is dependent upon the concentration of cytosolic flecainide, with 50% of maximal occurrence of block at 13.1 ± 1.9 μM (n=6). Crucially though, flecainide, even at supra-physiological concentrations (50 μM), had no effect on the physiologically relevant SR to cytosol cation flux through RyR2, producing no noticeable blocking events. This was found to be the case when using K+ as the charge carrying species to maximize the resolution of RyR2 gating and block (n=6) and under physiological salt conditions when Ca2+ was the permeant ion (n=3). Moreover, flecainide did not alter RyR2 gating with open probability and mean open and closed durations remaining unaltered (n=4-8). Flecainide (50 μM) had a negligible effect on the mechanisms responsible for the SR charge-compensating counter current; being unable to block the SR potassium channel (n=5) and only partially reducing the charge compensating K+ counter current through RyR2 (by 16.2 ± 3.84%, n=6). Using permeabilised rat cardiac myocytes to eliminate any contribution of plasmalemmal Na+ channels to the observed actions of the drug, flecainide did not inhibit RyR2-dependent SR Ca2+ release, producing no significant changes in Ca2+ spark and wave frequency or amplitude (n=19). We conclude that the principal action of flecainide in CPVT is via Na+ channel dependent modulation of intracellular Ca2+ cycling and not by a direct interaction with RyR2. Our data do not negate the clinical use of flecainide but serve to highlight that class Ic compounds should not be considered as prototypical RyR2 blockers.