LPS preconditioning requires TLR signaling through TRIF to promote neuroprotection. WT, MyD88-/-, and TRIF-/- mice were preconditioned with LPS (0.8 mg/kg) 3 days prior to 40 min MCAO. MyD88-/- mice were protected by LPS preconditioning resulting in smaller infarct sizes. TRIF-/- mice did not have reduced infarct sizes, demonstrating that TRIF deficient mice are not protected by LPS preconditioning. Thus, TRIF is required for LPS preconditioning induced neuroprotection. Student's t-test, LPS vs. saline, *p < 0.05, n = 4-10 per treatment.