OBJECTIVES: P-glycoprotein (P-gp), produced by the multidrug resistance (mdr1a) gene, is present in vascular endothelial cells, astrocytes, and microglia in the brain. We previously reported that P-gp aggravated cerebral infarct. Therefore, modulation of the function of P-gp is important for the treatment of brain ischemia. Here, we examined how P-gp exacerbates ischemic damage in the brain. METHODS: Experiments were performed using mdr1a knockout (KO) mice and wild-type mice. Mice of both groups were subjected to transient focal ischemia and Bcl-2 family proteins, p-glycoprotein and cytokines were measured. RESULTS: At 48 h after reperfusion, the expression of Bcl-2 protein in the brains of mdr1a KO mice was significantly greater compared with that of wild-type mice. The expression of brain Bax protein in mdr1a KO mice was significantly lower compared with that of wild-type mice. At 6 h after reperfusion, the expression of plasma IL-6 in mdr1a KO mice was significantly lower compared with that of wild-type mice. CONCLUSION: These results indicate that P-gp derived from the mdr1a gene has pro-apoptotic functions mediated through Bcl family proteins and increased IL-6, which exacerbates ischemic damage in the brain. In summary, the inhibition of P-gp function is an effective strategy to protect against brain damage caused by ischemic damage.