Insulin-like growth factor-II/mannose 6-P (IGF- II/M6P) receptor is released from cultured cells and tissues in a soluble form that retains its affinity for IGF-II. To test the possibility that soluble receptor can therefore modulate the activity of IGF-II, we determined the effect of purified soluble receptor on DNA synthesis in cultured rat hepatocytes stimulated with epidermal growth factor (EGF) (5 ng/ml) and IGF-II (200 ng/ml). Thymidine incorporation in hepatocytes in the presence of EGF and IGF-II was inhibited by soluble receptor (50% inhibition at 212 +/- 45 ng/ml). However, thymidine incorporation in the presence of EGF alone was also inhibited with similar potency. This inhibitory effect was removed by immunodepletion of receptor from the purified preparation, demonstrating the absence of nonspecific cytotoxic effects of the preparation. Although soluble receptor blocked IGF-II binding to hepatocytes, inhibition of EGF-stimulated DNA synthesis was not due to inhibition of EGF binding or uptake by the cell. These results suggest that soluble IGF-II/M6P receptor not only plays a role in modulating the action of IGF-II but may also have IGF-independent actions on cells, possibly by modulating M6P protein action.