The root of Paeonia lactiflora Pall. (Chishao, CS) and Ligusticum chuanxiong Hort. (Chuanxiong, CX) were widely used as a drug pair in Chinese Medicine, and the combination of CS and CX showed a more significant inhibition on neuronal apoptosis in our previous study. In the present study, total paeony glycosides (TPGs) from CS and total ligustici phenolic acids (TLPAs) from CX were combined to evaluate the synergistic effects against focal cerebral ischemia both in vitro and in vivo. The combination of TPGs and TLPAs at 7:3 had the best anti-oxidative stress and anti-inflammatory effect on OGD-induced HUVEC. Additionally, the infarction area proportion and neuron apoptosis of rats by TPGs:TLPAs (7:3) was significantly lower than their alone in MCAO rats. Moreover, TPGs: TLPAs of 7:3 showed a more significant effect on decreasing the expression of MMP-2 and MMP-9, and increasing the protein expression or mRNA level of TIMP-1 than other combinations. The optimal ratio of TPGs and TLPAs at 7:3 could bring more remarkable protective effects against focal cerebral ischemia in MCAO rats by alleviating oxidative stress, inflammatory and neuronal apoptosis to protect the blood-brain barrier. Overall, the present study provided benefical evidence for clinical application of CS and CX as a "drug pair". As the third highest worldwide cause of mortality 1 , stroke has been treated using antithrombotic therapy 2 , anticoagulant therapy 3,4 , neuroprotective and vascular dilated therapy. Numerous studies have demonstrated that the severity of neuronal apoptosis was associated with neurofunction, indicating a crucial role in the prognosis of ischemic stroke sufferer 5. Early anti-inflammatory and anti-oxidative stress may promote apoptosis of nerve cells. Thus attenuating these potential damage of nerve cells in ischemic area will be an effective strategy in clinical application. Chinese medicine (CM) has been used to treat stroke for a long time. Many classical prescriptions for treating cerebral diseases, such as Xiao-xu-ming decoction 6 are still being commonly used in modern clinial both in China and in other countries 7,8. Paeonia lactiflora Pall. (Chinese name: Chishao, CS) has been used worldwide for centuries and reported to exhibit various pharmacological bioactivities including anticoagulation, cognition enhancement, immunoregulatory 9 and anticance 10 , antioxidative 11 , and antidiabetic properties 12. The ischemic stroke protection of Paeoniae Radix may be related to its anti-oxidative stress and improvement of brain microcirculation. Ligusticum chuanxiong Hort. (Chinese name: Chuanxiong, CX) which belongs to the Umbelliferae family, is a valuable medicinal herb used worldwide and has been used for the treatment of atherosclerosis, hypertension, angina pectoris, and anti-inflammatory via acilitating blood circulation and dispersing blood stasis 13. Our previous study revealed the combination of CS and CX exerted more remarkable protective effects than alone by attenuating ER-stress-dependent apoptotic signaling and...