We originally reported the use of vitamin E (α-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with α-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons. After direct intracerebroventricular (ICV) infusion of Toc-siRNA/HDL for 7 days, extensive and specific knock-down of a target gene, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), was observed in both mRNA and protein levels, especially in the cerebral cortex and hippocampus. This new delivery method achieved a much more prominent down-regulation effect than conventional silencing methods of the brain gene, i.e., ICV infusion of nonconjugated siRNA or oligonucleotides. With only 3 nmol Toc-siRNA with HDL, BACE1 mRNA in the parietal cortex could be reduced by ∼ 70%. We suppose that this dramatic improvement of siRNA delivery to the brain is due to the use of lipoprotein receptor-mediated endocytosis because the silencing efficiency was significantly increased by binding of Toc-siRNA to the lipoprotein, and in contrast, was clearly decreased in lipoprotein-receptor knockout mice. These results suggest exogenous siRNA could be used clinically for otherwise incurable neurological diseases.