HIV-derived lentiviral vectors are efficient vehicula to deliver genes into the brain and hold great promise for future gene therapy of neurodegenerative disorders. However, administration of the current vector preparations in mouse brain was found to induce a systemic immune response to vector proteins and a modest inflammation in the brain. Moreover, serum antibodies from vector-treated animals were capable of partially neutralizing lentiviral vector-mediated transduction in cell culture. To avoid this unexpected immune reaction, we have optimized new vector production and purification protocols. Purification by sucrose gradient ultracentrifugation abolished the immune response, but vector titers also decreased substantially. Lentiviral vector production in the absence of serum in the cell culture medium equally reduced immunogenicity without affecting transduction efficiency. These results have important implications for future clinical use of lentiviral vectors, and for the use of lentiviral vectors to create animal models for neurodegenerative diseases that have an important neuroinflammatory component.