The existence of an immunological blood-brain barrier to homologous blood-borne immunoglobulin G (IgG) was investigated in the guinea pig using a vascular brain perfusion technique in situ. Cerebrovascular unidirectional transfer constants (Kin) for 125I-labeled IgG (2.5 micrograms/ml) estimated from the multiple-time brain uptake data, ranged from 0.53 to 0.58 ml min-1 g-1 X 10(3) in the parietal cortex, hippocampus, and caudate nucleus, the transfer rate being some 10 times higher than that for [3H]dextran (MW 70,000). In the presence of 4 mg/ml unlabeled IgG, unidirectional blood to brain transfer of 125I-IgG was markedly inhibited. Immunohistochemical analysis of the brain tissue after vascular perfusion with unlabeled IgG revealed a distribution of the blood-borne immunoglobulin in the endothelial cells of microvessels and in the surrounding perivascular tissue. It is concluded that there is a specific transfer mechanism for IgG at the blood-brain barrier in the guinea pig, which is saturated at physiological plasma levels of IgG.