['To investigate the clinical significance of cyclic adenosine monophosphate-responsive element-binding (CREB) and phosphorylated CREB (pCREB) expression in human hepatocellular carcinoma (HCC).', 'Immunohistochemistry and Western blot analyses were performed to detect the expression and subcellular localizations of CREB and pCREB proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues.', 'Both immunohistochemistry and Western blot analyses showed that the expression levels of CREB and pCREB proteins in HCC tissues were significantly higher than those in the adjacent nonneoplastic liver tissues (both P<0.001). In addition, the combined upregulation of CREB and pCREB proteins (CREB-high/pCREB-high) was significantly associated with serum α-fetoprotein (P=0.02), tumor stage (P<0.001), and tumor grade (P=0.01). Moreover, HCC patients with CREB-high/pCREB-high expression showed shortest 5-year disease-free survival and 5-year overall survival (both P<0.001). Furthermore, the multivariate survival analysis found that the combined upregulation of CREB and pCREB proteins may be an independent unfavorable prognostic factor for both 5-year disease-free survival and 5-year overall survival (both P=0.01) in HCC.'] Does cyclic adenosine monophosphate-responsive element-binding protein activation predict an unfavorable prognosis in patients with hepatocellular carcinoma?