Aim Phosphatidylinositol 3-kinase (PI 3-kinase), one of the signal-transducing molecules containing SH2 domain, can be activated by binding to growth factor receptors and transmits intracellular signals involved in cell growth as well as cellular transformation. This study was performed to determine whether PI 3-kinase is activated in vivo and in vitro and therefore may contribute to cell growth and transformation of the liver. Methods Liver tissue and cell homogenates were prepared with lysis buffer from 1) rat regenerating livers after partial hepatectomy (PH) 2) rat primary cultured hepatocytes under growth factor (s) stimulation 3) human liver cancer cell lines. The homogenates were reacted with anti PI 3-kinase antibody (Ab), or anti growth factor receptor Abs to determine total, or partial enzymatic activity, respectively. Association of PI 3-kinase with growth factor receptors were assessed by immuno-precipitation followed by Western blotting. Results Total PI 3-kinase activity was enhanced from 2 hr to 18 hr after PH, prior to the major wave of DNA synthesis with a peak at 6 hr in the regenerating rat liver. Partial PI 3-kinase activity in the immunoprecipitates with anti insulin receptor substrate 1(IRS-1) Ab, anti HGFR (receptor) Ab, anti EGFR Ab was sequentially enhanced with a peak at 2 and 12 hr, 6 hr, 10 hr, respectively, indicating that integrated partial activities may account for total activity of PI 3-kinase. Activation of partial PI 3-kinase was observed in parallel with association with the corresponding growth factor receptors. In addition, activation of PI 3-kinase in rat cultured hepatocytes and human hepatoma cell lines induced by growth factors (EGF, insulin, HGF) was reduced by the specific inhibitor of PI 3-kinase, followed by the inhibition of DNA synthesis. Conclusion Activation of PI 3-kinase may play an important role in hepatocyte growth and hepatocellular transformation.