Cardiac calsequestrin–null mice (Casq2^−/−) display catecholaminergic ventricular tachycardia akin to humans with CASQ2 mutations. However, the specific contribution of Casq2 deficiency to the arrhythmia phenotype is difficult to assess because Casq2^−/− mice also show significant reductions in the sarcoplasmic reticulum (SR) proteins junctin and triadin-1 and increased SR volume. Furthermore, it remains unknown whether Casq2 regulates SR Ca²⁺ release directly or indirectly by buffering SR luminal Ca²⁺. To address both questions, we examined heterozygous (Casq2^+/−) mice, which have a 25% reduction in Casq2 but no significant decrease in other SR proteins. Casq2^+/− mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2^+/+ mice (n=31; P<0.05). Programmed stimulation induced significantly more ventricular tachycardia in Casq2^+/− mice than in Casq2^+/+ mice. Field-stimulated Ca²⁺ transients, cell shortening, L-type Ca²⁺ current, and SR volume were not significantly different in Casq2^+/− and Casq2^+/+ myocytes. However, in the presence of isoproterenol, SR Ca²⁺ leak was significantly increased in Casq2^+/− myocytes (Casq2^+/− 0.18±0.02 F_ratio versus Casq2^+/+ 0.11±0.01 F_ratio, n=57, 60; P<0.01), resulting in a significantly higher rate of spontaneous SR Ca²⁺ releases and triggered beats. SR luminal Ca²⁺ measured using Mag-Fura-2 was not altered by Casq2 reduction. As a result, the relationship between SR Ca²⁺ leak and SR luminal Ca²⁺ was significantly different between Casq2^+/− and Casq2^+/+ myocytes (P<0.01). Thus, even modest reductions in Casq2 increase SR Ca²⁺ leak and cause ventricular tachycardia susceptibility under stress. The underlying mechanism is likely the direct regulation of SR Ca²⁺ release channels by Casq2 rather than altered luminal Ca²⁺.