Along with redistributive shock, myocardial dysfunction is now recognized as highly prevalent in early severe sepsis. Indeed, aside from their distinct loading potency, resuscitation fluids have been poorly investigated as to their specific molecular impact on myocardial dysfunction. The objective of this study was to evaluate the load-independent biological impact of different resuscitation fluids on endotoxin-induced myocardial dysfunction. Adult rats implanted with a central venous catheter were given an intraperitoneal injection of endotoxin (lipopolysaccharides [LPSs], Escherichia coli, 10 mg/kg) or normal saline (sham) and subsequently infused or not with similar "fluid potency" loading resuscitation fluid (normal saline, albumin [Alb], or hypertonic saline solution) for 6 to 24 h, followed by echocardiographic and hemodynamic monitoring together with biochemical and histopathologic evaluation. Intervention was to assess the selective influence of load-independent fluid infusion on the aforementioned parameters in groups of animals challenged or not with LPS. At comparative plasma volumes, Alb improved myocardial homeostasis after LPS challenge by (i) reducing left ventricular relative wall diastolic thickness, interstitial space enlargement, and endogenous Alb content; (ii) limiting cardiac apoptosis and sustaining extracellular signal-regulated mitogen-activated protein kinase activation; and (iii) enhancing the expression pattern of heme-oxygenase 1/inducible nitric oxide synthase. Hypertonic saline solution was also cardioprotective by early prevention of myocardial dysfunction and by reducing cardiac apoptosis. Fluid infusions have distinct load-independent structural/biological impacts on endotoxin-induced myocardial dysfunction. Albumin and hypertonic saline solution are the most pleiotropic fluids in protecting the heart after a "sepsis" hit.