Monoclonal antibodies to the human transferrin receptor were screened for binding to capillary vessels in human, monkey, rabbit and rat brain tissue. Two antibodies were selected that bind both human and monkey but not rabbit or rat microvessels. With recombinant fragments of the human receptor, both antibodies were shown to bind to a region of the extracellular portion of the receptor that is relatively variable among species. Binding, which was characterized by using purified receptor and K562 cells, was not reduced by excess transferrin, indicating that the antibodies bind the receptor at a site different from that of transferrin. When the antibodies were radiolabeled and injected i.v. into cynomolgous monkeys, they distributed selectively to brain but not to other organs or tissues. The antibodies were found almost exclusively in the brain parenchyma, rather than the capillaries, indicating that they had transcytosed the blood-brain barrier. These results show that antibodies to the human transferrin receptor cross the blood-brain barrier and may be useful for noninvasive delivery of therapeutic proteins to the central nervous system.