The soluble type 2 insulin-like growth factor (IGF) receptor or IGF-II/mannose 6-phosphate receptor (sIGF2R) is produced in vivo by proteolytic deletion of the transmembrane and intracellular domains of the cellular form of the receptor (IGF2R). There is evidence that sIGF2R is a negative regulator of growth. We have shown that transgenic mice expressing an Igf2r cDNA with a deleted transmembrane domain sequence (sDeltaIgf2r) show reduced local organ size. In the present study, we investigate whether sDeltaIGF2R can slow the growth induced by an excess of IGF-II and whether the biological activity of sDeltaIGF2R is due solely to its interactions with IGF-II. To this end, we crossed sDeltaIgf2r transgenics by mice overexpressing IGF-II (Blast line) or by mice carrying a disrupted paternal (active) allele of the Igf2 gene (Igf2(m+/p-)). Analysis of the phenotypes revealed that the soluble IGF2R affects the size of some organs (colon and cecum) exclusively by reducing the biological activity of IGF-II, whereas in other organs (stomach and skin) the biological activity of the receptor is at least in part independent of IGF-II and must involve an interaction with other factor(s).