Purpose: The Janus kinase 2 (JAK2) pathway plays an important role in cardiac signalling. Although the contribution of JAK2 to cardiac pathology is unclear, the failing human myocardium is associated with depressed JAK2-dependent STAT3 activation. We therefore studied the consequence of cardiac-specific JAK2 deletion on the heart. Methods. As global JAK2 deletion is embryonic-lethal, we generated mice with cardiac-specific disruption of the JAK2 gene using the Cre-loxP system in which homozygous Jak2 fl/fl mice were mated to heterozygous α-MHC Cre+/- mice. These mice (JAK2-KO) survived to birth, were visibly indistinguishable from their wild type littermate (JAK2-WT) controls and demonstrated cardiac specific JAK2 deletion determined by genotyping and Western blotting. Mice were followed for 4 months after birth and analyzed monthly by serial echocardiography. Other animals were sacrificed monthly and hearts were analyzed for cardiac-specific changes. Results. Body weights of KO and WT mice were identical although heart weights in KO mice were higher as was the expression of two molecular markers of hypertrophy, ANP and α-skeletal actin. Moreover, serial echocardiography revealed progressive deterioration of left ventricular (LV) function including a reduction in ejection fraction (at 4 months: 73 ± 2.5% in WT vs 33 ± 3.3% in KO, P<0.01). Other indices (all values at 4 months) including fractional shortening (41 ± 2.4% in WT vs 22 ± 1.9% in KO, P<0.01), cardiac output (12.3 ± 4.0 ml/min in WT vs 4.7 ± 0.7 ml/min in KO, P<0.05) and stroke volume (23.4 ± 5.8 μl in WT vs 10.8 ± 1.8 μl in KO, P<0.05) were equally depressed in JAK2-KO mice throughout the 4 month period. Kaplan-Meier analysis revealed mortality, likely due to sudden death, throughout the 4 month period which reached 42% at 4 months (P<0.05) with no deaths observed in JAK2-WT animals at any time. Hearts from JAK2-KO mice showed a significant reduction in STAT3 phosphorylation. In addition, myocardial immunofluorescence staining for connexin 43 was significantly reduced compared to WT mice. Hearts from these mice also showed a significant reduction in the protein expression levels of vinculin, a 117 kDa membrane bound protein which exerts important roles in cardiomyocyte integrity, function and cell-cell communication. Conclusions. Our results show for the first time that selective cardiac deletion of JAK2 produces a distinct phenotype of severe LV dysfunction associated with hypertrophy and significant mortality.These findings may offer a basis for identifying a role for JAK2 in cardiac pathology, particularly heart failure.