The etiology of hepatic insufficiency associated with the multiple systems organ failure (MSOF) syndrome is unclear. The authors have investigated the possibility that a macrophage/Kupffer cell mediated modulation of hepatocyte function may play a role in this phenomenon. Isolated rat hepatocytes were cultured, and their rate of protein synthesis was measured by cpm of 3H leucine incorporation into protein. Nonparenchymal rat liver cells (NPC) comprised of 35-40% Kupffer cells were added to hepatocytes to establish a co-culture with or without endotoxin. Neither NPC alone nor endotoxin alone affected hepatocyte protein synthesis. However, in the presence of endotoxin, NPC caused a marked diminution of hepatocyte protein synthesis (4,396 +/- 449 cpm) compared with control hepatocytes (10,943 +/- 623 cpm). No change in microscopic morphology or ability to exclude trypan blue occurred. This modulation of hepatocyte function by an endotoxin stimulated Kupffer cell preparation may, in part, represent the mechanism of hepatic insufficiency associated with the MSOF syndrome.