ABSTRACT— To investigate the possibility that a “spillover effect” of substances from the portal vein into the systemic circulation accounts for the abnormal monocyte function in patients with liver disease, we have incubated human peripheral blood monocytes with paired specimens of portal and systemic serum from humans and rabbits. Monocytes incubated with portal serum released more of a lysosomal enzyme, N-acetyl-B-glucosaminidase, than those incubated with systemic serum (p<0.05). In order to delineate the factors responsible for this increased activity, the content of immune complexes, immunoglobulins and endotoxin in the paired specimens of portal and systemic serum was measured. Endotoxin was found in none of 16 human specimens of portal blood and five of the 16 rabbit specimens. Modestly increased levels of immune complexes, particularly of the IgG class, were found in the portal serum compared to the systemic serum (p<0.01). Corresponding studies on immunoglobulins showed a higher concentration of IgA in portal serum (p<0.05), but no difference in other classes of immunoglobulins or complement levels. There was good correlation between the enzyme production by monocytes and the concentration of immune complexes, particularly IgA (r=0.687, p<0.001), but there was no relationship to the presence or absence of endotoxin. This evidence suggests that portal serum contains substances, particularly immune complexes, which under normal circumstances are sequestered by the liver. These are capable of “activating” monocytes in vitro and may play a role in the pathogenesis of certain types of liver disease.