The liver is reported to be the main source of soluble insulin-like growth factor-II/mannose 6-phosphate (IGF-II/M6P) receptor in adults. In view of the role of this receptor in the activation of transforming growth factor β (TGF-β) during hepatic fibrogenesis, we have investigated the correlation between serum levels and tissue expression of the receptor during acute CCl4 intoxication of the rat. Sixteen hours after CCl4, injection, the level of the soluble receptor in serum, as measured by radioimmunoassay (RIA), increased threefold. At 24 hours, values almost returned to normal, but increased again by twofold at 48 hours. By 96 hours, nearly normal values were obtained. Northern blot analysis showed peaks in tissue IGF-II/M6P receptor messenger RNA (mRNA) levels at 24 hours and at 48 hours. In normal liver, immunostaining for IGF-II/M6P receptor showed weak positivity in parenchymal cells. CCl4-induced hydropic changes appeared in centrilobular parenchymal cells (PCs) at 8 hours. These changes extended to the midzonal region at 16 hours. Hydropic cells were devoid of receptor staining. The hydropic wave became extinct at 32 hours. At 48 hours, we observed a collapse of PCs in the centrilobular zone, coinciding with strongly positive staining for IGF-II/M6P receptor in fat-storing cells (FSCs), identified by dual IGF-II/M6P receptor and desmin immunostaining. Between 48 and 72 hours, the liver gradually regained its normal appearance. As shown by Western blotting, in vitro differentiated FSCs released soluble receptor in the medium. Northern blot analysis showed this release to be preceded by an increased receptor-mRNA expression, whereas immunostaining showed an increase of intracellular receptor. In conclusion, we have shown that acute CCl4 intoxication induces two peaks in serum levels of soluble receptor. While the first peak at 16 hours coincides with the loss of receptor- staining in hydropically damaged PCs, the second peak at 48 hours is paralleled by an increase in positive staining in FSCs and tissue mRNA level. Differentiated FSCs shed soluble receptor in vitro. As a consequence, these cells might contribute to the serum levels of soluble receptor in vivo. These results indicate that measuring serum soluble IGF-II/M6P receptor might useful in the diagnosis of early acute liver damage.