Rat monoclonal antibodies, used in immunocytochemistry of normal rat brain, result in a granular reaction product within neurons innervating areas lacking a blood-brain barrier. Immunocytochemical characterization shows that the staining is independent of the primary antibody and exclusively dependent on the presence of anti-rat immunoglobulin. This granular staining could be selectively eliminated by pre-adsorption of the anti-rat immunoglobulin with purified rat immunoglobulin or disruption of microtubule retrograde transport systems by intraventricular injection of colchicine. A dependence on retrograde transport and complete independence from local synthesis was further substantiated by the rapid uptake and accumulation of intravenously administered rabbit or rat [125I]immunoglobulins by the supraoptic-neurohypophysial system. Immunoelectron microscopy was used to identify the endogenous rat immunoglobulin within lysosome-like organelles in the cytoplasm of magnocellular neuroendocrine cells. The uptake and incorporation of plasma macromolecules into the lysosomal system of magnocellular and other neurons projecting to regions with a weak blood-brain barrier may represent a novel mode of blood-central nervous system interactions.