BACKGROUND AND PURPOSE Notoginsenoside R1 (NG-R1), a novel phytoestrogen isolated from Panax notoginseng, is believed to have anti-inflammatory, anti-oxidative and anti-apoptotic properties. However, its cardioprotective properties and underlying mechanisms are largely unknown. Here we have assessed the contribution of the anti-inflammatory effects of NG-R1 to the amelioration of septic cardiac dysfunction and inflammation in mice. EXPERIMENTAL APPROACH We assessed cardiac function in mice by echocardiography. We studied the protein or mRNA levels of some inflammatory factors, apoptotic factors and oestrogen receptors (ERs) in heart tissues upon stimulation with bacterial LPS, NG-R1 or some pharmacological inhibitors. KEY RESULTS Six hours after LPS administration (10 mg·kg-1, i.p.) cardiac function was decreased, an effect attenuated by NG-R1 pretreatment (25 mg·kg-1·d-1, i.p.). NG-R1 also improved the imbalance between iNOS and eNOS, prevented activation of NF-kB and the subsequent myocardial inflammatory and apoptotic responses in endotoxemic mice. The effects of NG-R1 were closely associated with activation of the oestrogen receptor ERa and of PI3K/PKB (Akt) signalling, as characterized by NG-R1-induced preservation in ERa, phospho-Akt, phospho-GSK3b and I-kBa, and of cardiac function that was partially blocked by selective inhibitors of ERa or PI3K. However, NG-R1 had no effect on LPS-activated TLR-4. CONCLUSIONS AND IMPLICATIONS NG-R1 is a promising compound for protecting the heart from septic shock, possibly via the activation of ERa and PI3K/Akt signalling. This mechanism produces blockade of NF-kB activation and attenuation of the pro-inflammatory state and apoptotic stress in the myocardium.