Oval cells are small nonparenchymal epithelial cells that first appear in the periportal areas of the liver and thereafter invade the whole parenchyma when mice or rats are exposed to a variety of chemical carcinogens. In the present study we have analyzed the expression of insulin-like growth factor II (IGF II) in the recently established oval cell line OC/CDE 22 and its malignantly transformed counterpart (the M22 cells) and the biological consequences of the constitutive expression of IGF II in oval cells. OC/CDE 22 cells do not express the above-mentioned growth factor, whereas the M22 cells do and addition of a neutralizing anti-IGF II antibody to M22 cells resulted in an almost complete proliferation stop. The presence of type 1 as well as type 2 insulin-like growth factor receptors in OC/CDE 22 and M22 cells was revealed by Northern blotting; however, only neutralizing antibodies directed against the type 1 IGF receptor were able to inhibit the proliferation of the cultured oval cells. Finally, transfection of an IGF II complementary DNA (cDNA) into OC/CDE 22 cells resulted in the release of active IGF II into the extracellular medium but not in the concomitant malignant transformation of the cells. Taken together these results show that: 1) upon transformation oval cells start producing IGF II and 2) IGF II acts on oval cells as a pure mitogen (without being per se oncogenic) via an autocrine loop involving the activation of the type 1 IGF receptor.