It is proposed that interleukin 1 (IL 1) and tumor necrosis factor (TNF) alpha play central roles in the host's response to inflammation. Yet circulating concentrations have not been frequently measured in many inflammatory states. Serum levels of IL 1 and TNF were evaluated in mice with a tumor, sterile inflammation, endotoxinemia, or generalized peritonitis where an acute-phase protein response was documented. In tumor-bearing mice, no IL 1 or TNF could be detected despite marked increases in the serum concentration of the acute-phase reactant protein, amyloid P. In mice with peritonitis, induced by cecal ligation and perforation, or a turpentine-induced subcutaneous abscess, IL 1 but not TNF could be detected in the serum. Only expansion of the reticuloendothelial system with Corynebacterium parvum and subsequent challenge with endotoxin resulted in serum TNF appearance. The failure to observe IL 1 or TNF in any of the disorders could not be explained by inhibitors. Rather, the data suggest that a hepatic acute-phase protein response can occur during inflammatory states without the appearance of either IL 1 or TNF in the circulation. Circulating levels of both monokines do not appear to be a universal finding in inflammation.