Background— Phosphoinositide 3-kinase γ (PI3Kγ) signaling engaged by β-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3Kγ in catecholamine-induced arrhythmia is currently unknown. Methods and Results— Mice lacking PI3Kγ (PI3Kγ ^−/− ) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective β ₂ -adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after β ₂ -adrenergic receptor activation in PI3Kγ ^−/− cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3Kγ. Downstream from β-adrenergic receptors, PI3Kγ was found to participate in multiprotein complexes linking protein kinase A to the activation of phosphodiesterase (PDE) 3A, PDE4A, and PDE4B but not of PDE4D. These PI3Kγ-regulated PDEs lowered cAMP and limited protein kinase A–mediated phosphorylation of L-type calcium channel (Ca _v 1.2) and phospholamban. In PI3Kγ ^−/− cardiomyocytes, Ca _v 1.2 and phospholamban were hyperphosphorylated, leading to increased Ca ²⁺ spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kγ ^−/− cardiomyocytes showed spontaneous Ca ²⁺ release events and developed arrhythmic calcium transients. Conclusions— PI3Kγ coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.