Antibody-based therapeutics targeting CNS antigens emerge as promising treatments in neurology. However, access to the CNS is limited by the blood-brain barrier. We examined the effects of a neurite growth-enhancing anti-Nogo A antibody therapy following 3 routes of administration-intrathecal (i.t.), intravenous (i.v.), and subcutaneous (s.c.)-after large photothrombotic strokes in adult rats. Intrathecal treatment of full-length IgG anti-Nogo A antibodies enhanced recovery of the grasping function, but intravenous or subcutaneous administration had no detectable effect in spite of large amounts of antibodies in the peripheral circulation. Thus, in contrast to intravenous and subcutaneous delivery, intrathecal administration is an effective and reliable way to target CNS antigens. Our data reveal that antibody delivery to the CNS is far from trivial. While intrathecal application is feasible and guarantees defined antibody doses in the effective range for a biological function, the identification and establishment of easier routes of administration remains an important task to facilitate antibody-based future therapies of CNS disorders.