We investigated the possibility that monocyte suppressor cells play a role in the peripheral lymphocyte hyporesponsiveness of chronic liver disease by utilizing assays of monocyte-mediated suppressor activity in 46 patients with chronic liver disease and 46 controls. The percent change achieved by the addition of indomethacin to a PHA-induced proliferative response was significantly increased in patients with cirrhosis compared with controls (p less than 0.001). The increase was seen in cirrhosis regardless of etiology but was not found in patients with chronic hepatitis without cirrhosis. The effects of indomethacin were abolished by monocyte depletion and were greater in autologous serum than in pooled AB serum (p less than 0.02). Monocyte depletion in cirrhotic patients significantly increased the lymphocyte response to PHA (p less than 0.005) but made no significant difference in controls. There was a significant correlation between the indomethacin-induced changes and the changes in lymphocyte response to PHA on monocyte depletion (r = 0.6583, p less than 0.01). Our initial results led us to study the mode of action of the inhibitory effect of cirrhotic serum on lymphocyte response to PHA. Cirrhotic serum significantly reduced the response of normal lymphocytes compared with control serum (p less than 0.02), but the difference was abolished by adding indomethacin and by monocyte depletion. These results suggest that monocyte suppressor cells may play a role in the depressed cellular immunity seen in some patients with cirrhosis. The inhibitory effect of cirrhotic serum appears to be in part monocyte mediated and prostaglandin dependent.