Previous reports indicate IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that IL-18 mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared to control (CTR) mice, a "humanized" mouse model of SCD exhibited increased cardiac fibrosis, prolonged action potential duration (APD), higher VT inducibility in vivo, higher cardiac NFκB phosphorylation and circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, translating to reduced outward potassium current (Ito) in isolated cardiomyocytes. IL-18 administration to isolated mice hearts resulted in VTs, originating from the right ventricle, and further reduced Ito in SCD mice cardiomyocytes. Sustained IL-18 inhibition via IL-18 binding protein resulted in decreased cardiac fibrosis and NFκB phosphorylation, improved diastolic function, normalized electrical remodeling and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMC), with QTc strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in non-surviving over surviving subjects. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.