Oxymatrine is one of the alkaloids extracted from the Chinese herb Sophora japonica (Sophora flavescens Ait.) with anti-inflammatory, immune reaction inhibiting, antiviral, and hepatocyte and antihepatic fibrosis protective activities. However, the effect of oxymatrine on heart failure is not yet known. In this study, the effect of oxymatrine on heart failure was investigated using a Sprague-Dawley rat model of chronic heart failure. Morphological findings showed that in the group treated with 50 and 100 mg/kg of oxymatrine; intermyofibrillar lysis disappeared, myofilaments were orderly, closely and evenly arranged; and mitochondria contained tightly packed cristae compared with the heart failure group. We investigated the cytosolic Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) content, and assessed the expression of ryanodine receptor (RyR2), SR-Ca(2+) ATPase (SERCA2a), and L-type Ca(2+) channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca(2+) transients were markedly increased in amplitude in the medium- (ΔF/F (0) = 26.22 ± 2.01) and high-dose groups (ΔF/F (0) = 29.49 ± 1.17) compared to the heart failure group (ΔF/F (0) = 12.12 ± 1.35, P < 0.01), with changes paralleled by a significant increase in the SR Ca(2+) content (medium-dose group: ΔF/F (0) = 32.20 ± 1.67, high-dose group: ΔF/F (0) = 32.57 ± 1.29, HF: ΔF/F (0) = 17.26 ± 1.05, P < 0.01). Moreover, we demonstrated that the expression of SERCA2a and cardiac DHPR was significantly increased in the medium- and high-dose group compared with the heart failure rats. These findings suggest that oxymatrine could improve heart failure by improving the cardiac function and that this amelioration is associated with upregulation of SERCA2a and DHPR.