ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter in the central nervous system, plays an important role in the formation of brain HDL-cholesterol. ABCA1 is up-regulated by the transcription factors, liver X receptors (LXRs). Our previous study using brain-specific ABCA1 deficient (floxed, nestin-Cre positive, ABCA1-B/-B) and ABCA1 floxed-control (ABCA1fl/fl) mice showed that ABCA1 has anti-inflammatory effects and reduces white matter (WM) damage in ischemic stroke models. Here, we further test whether GW3965, a synthetic LXR agonist treatment of stroke increases ABCA1 and HDL, and thereby improves WM-remodeling and functional outcome. Adult male ABCA1fl/fl and ABCA1-B/-B mice were subjected to permanent extraluminal distal middle cerebral artery occlusion (dMCAo) by transcranial ligation method. Animals were gavaged with saline or GW3965 (10 mg/kg) starting 24h after dMCAo and daily till sacrificed 14 days after dMCAo. There were no differences in the lesion volume and blood levels of total cholesterol and triglyceride before and after dMCAo between ABCA1-B/-B and ABCA1fl/fl mice. However, GW3965 treatment significantly increased blood HDL levels in ABCA1fl/fl mice, but not in ABCA1-B/-B mice 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl stroke mice, but not in ABCA1-B/-B stroke mice, also increased: 1) WM-density identified by Luxol Fast Blue (myelin marker), Bielshowsky silver (axon marker), and SMI31 (phosphorylated neurofilament marker) staining; 2) the number of platelet-derived growth factor receptor alpha positive oligodendrocyte progenitor cells; 3) ABCA1, synaptophysin and myelin basic protein expression in the ischemic brain; 4) functional outcome 7 and 14 days after dMCAo, compared with non-treatment ABCA1fl/fl stroke mice (p<0.05, n=9/group). GW3965 and HDL treatment significantly increase axonal/neurite outgrowth in cultured primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. Treatment of stroke with GW3965 significantly increased blood level of HDL, increased ABCA1 expression and WM-remodeling in the ischemic brain. Increasing ABCA1 may contribute to GW3965 induced neurorestoration and WM remodeling after stroke.