In the presence of oxidative stress, the hepatocellular inflammatory-redox (IR) state upregulates inducible nitric oxide synthase (iNOS) expression as an anti-oxidant function. In IL-1beta and peroxide treated hepatocytes, we have identified hepatocyte nuclear factor-4alpha (HNF4) and the transcriptional co-activator, PC4, to be essential for upregulation of iNOS transcription in this setting. The co-activator, PC4, facilitates activator-dependent transcription via interactions with basal transcriptional machinery that are independent of PC4-DNA binding. The interaction between HNF4 and PC4 has not been previously characterized. In this study utilizing human HepG2 cells, we demonstrate the critical role for p38 MAP kinase mediated HNF4 Ser158 phosphorylation (P-HNF4-S158), binding of PC4 to P-HNF4-S158 and characterize the functional domain of PC4 required for P-HNF4-S158 binding. Our results indicate that the presence of the IR state enhances PC4-HNF4 binding to upregulate transcription of target hepatocyte genes, such as iNOS.