Somatostatin analogs treat acromegaly by lowering pituitary GH (GH) secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that somatostatin analog (SA), SOM230, can also act by a non-pituitary mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of IRS-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate insulin-like growth factor binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). IGF-I overcame this inhibition. Measurement of sst_1-5 by real time RT-PCR revealed that the mammary glands had an abundance of sst₃ and lower amounts of sst₄ and sst₅ but no sst₁ or sst_2. That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sst₂, strongly suggests that sst₃ is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel non-pituitary mechanism, 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect, and 3) Measurement of available sst receptors in the mammary gland suggests that sst₃ mediates the SA activity, but sst₅ is also a possible mediator.