The liver plays a crucial role in the acute phase response after injury; mechanisms responsible for transducing inflammatory signals to the nucleus to initiate this response are not known. The purpose of this study was to examine the induction of the novel Stat (signal transducer and activator of transcription) pathway in the liver after burn injury. Rats were subjected to either a 60% burn or sham treatment; livers were removed over a time course and extracted for nuclear protein. We found that Stat3, but not Stat5, binding was predominantly increased in the liver after burn injury as assessed by gel mobility and "supershift" analyses. Moreover, Stat3 nuclear protein levels were increased 6- to 14-fold in the livers of burned rats compared with those of sham rats. Stat3 phosphorylation was rapidly induced after burn injury; the subsequent increase of Stat3 binding was completely blocked by preincubation with the antiphosphotyrosine antibody (4G10). We conclude that a differential and early induction of Stat3 binding activity occurs in the liver after burn injury; this induction is mediated by an increase in phosphorylation. These findings suggest an important role for Stat3 in transducing inflammatory signals to the nucleus of liver cells after a systemic burn injury.