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The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5' untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after short-term treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GH-receptor positive CHO cells with P2 and P4 promoter-luciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.