In the rat, plasma IgA is rapidly endocytosed by hepatocytes and translocated to the bile via a receptor-mediated vesicular transport system which appears to remain intact even during cholestasis. During the latter phenomenon, there is an accumulation of secretory IgA (sIgA) in plasma. These data suggest that biliary IgA can be regurgitated into the plasma compartment. The present study was designed to determine the location and mechanism(s) by which this might occur. 125I-labeled human polymeric IgA (plgA) or slgA was infused retrograde into the rat common bile duct at a flow rate of 20 μ1 per min (5 to 10 μg per min pig A; 7 μg per min sIgA) over 1 hr. Blood and liver samples were collected 10, 30 and 60 min, and radioactivity determined. Radioactive label appeared in the blood by 10 min and increased linearly with time. By 30 min, however, the liver had reached saturation. All of the label found in the blood was intact starting material, i.e., plgA or slgA. Electron microscopic autoradiography analysis clearly demonstrated the presence of grains in vesicles in hepatocyte pericanalicular cytoplasm, as well as in vesicles near the sinusoidal plasma membrane. No grains were observed associated with bile duct or ductule epithelium at any time period. Further, there was no grain accumulation near the parenchymal cell intercellular spaces indicating that paracellular flow plays little or no role in large protein regurgitation. In addition, by 60 min, there were grains associated with Kupffer cells. These data provide the first evidence that hepatocytes, during times of elevated biliary pressure can readily transport macro-molecules from bile to plasma via nonreceptor-mediated membrane-limited vesicles.