We have demonstrated that two members of the acute phase reactant family of positively regulated genes, alpha 1-acid glycoprotein (AGP-1 and AGP-2) and C-reactive protein (CRP) are induced by hyperthermia, while two others, the serum amyloid A (SAA) and alpha 1-antitrypsin (AT) genes, are not. Albumin (ALB), a negative acute phase reactant gene, is also induced by hyperthermia. The AGP-1, AGP-2, and CRP genes require glucocorticoids, but not IL-6, IL-1 beta or TNF alpha in response to hyperthermia. As with LPS, the C/EBP beta mRNA levels increased, while the C/EBP alpha mRNA levels decreased in response to LPS. In contrast to the LPS response, C/EBP delta was unchanged. Protein pool levels and DNA-binding activities of the 35 and 20 kDa C/EBP beta isoforms increase, whereas protein pool levels of the 42 kDa C/EBP alpha decrease and the 30kDa remained high. These studies suggest that the synthesis of specific C/EBP alpha and C/EBP beta isoforms is induced by hyperthermia, and that the regulation of the AGP-1 and AGP-2 genes during heat stress may involve one of these isoforms. The difference between the responses to hyperthermia and LPS is that the former, may not involve the participation of cytokines. Furthermore, since cis-acting heat shock elements (HSE) are located in the promoter regions of the ALB, CRP, and C/EBP beta genes, these regulatory sequences may be involved in the in vivo activation of these genes by hyperthermia.