SUMMMARY The importance of insulin-like growth factor I (IGF-1) on maintenance of skeletal integrity has been widely recognised. Although osteoblasts secrete some IGF-1, the liver is the primary endocrine source for IGF-1. We have studied the regulation of the human IGF-1 promoter in the hepatocytic cell line Hep-3B, and have shown that the IGF-1 promoter, when cotransfected in Hep-3B cells together with an estrogen receptor- (ER-)-expression vector, was transcriptionally regulated by raloxifene or raloxifene like molecules but not by 17-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonised by 17-estradiol and is mediated selectively by ER, not by ER. Transfer of IGF-1 promoter sequences from -733 to -65 or -375 to -65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains two C/EBP sites and an AP-1 site, both of which have been shown to be involved in estrogen receptor mediated transactivation. When the C/EBP sites were mutated in a construct bearing the sequence from –375 to –65 in front of the minimal Fos promoter raloxifene induction was reduced while mutation of the other elements did not affect induction. In addition using chimeric proteins we delineated the domains of ER which confer to ER transactivation abilities on the IGF-1 promoter that are not exhibited by ER. These data shed new light on the mechanism of action of antiestrogens and might help explain -at least in part- the bone protective effects observed for some antiestrogens in ovariectomized animals.