Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGCα₁-deficient (sGCα₁^−/−) mice to unequivocally determine the role of sGCα₁β₁ in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGCα₁^−/− mice on the C57BL/6 background (sGCα₁^−/−B6 mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGCα₁^−/−B6 than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca²⁺ handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGCα₁^−/−B6 than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGCα₁^−/−B6 compared with WT mice. Together, these findings suggest that cGMP generated by sGCα₁β₁ protects against cardiac dysfunction and mortality in murine inflammatory shock models.