Monoclonal antibodies (MAbs) directed against cell surface receptors (e.g. the transferrin receptor or the insulin receptor) on the brain capillary endothelium, which makes up the blood-brain barrier (BBB) in vivo, are brain drug-delivery vectors. When cells are chronically exposed to MAbs in tissue culture, there is often down-regulation of the cell surface receptors. To examine whether similar down-regulation occurs in vivo, rats were chronically treated either with the OX26 murine MAb to the rat transferrin receptor or with a mouse IgG2a isotype control (0.25 mg/kg sc daily for 1 week), and the BBB transport of the OX26 MAb was then measured for both rat brain and liver in vivo. Although this treatment regimen resulted in a 41% increase in the permeability-surface area product for ¹²⁵I-OX26 MAb transport into rat liver in vivo, there was no significant change in the BBB permeability-surface area product for the OX26 MAb. These studies indicate that repetitive administration of cell surface-specific MAbs does not necessarily result in down-regulation of BBB receptors.