IGF-I has been shown to enhance insulin sensitivity in patients with type I and type II diabetes. IGF-I suppresses GH, and this raises the question of whether its ability to enhance insulin sensitivity is mediated solely through a reduction in GH’s antiinsulin actions. This study was conducted to determine whether administration of a GH receptor antagonist to patients with acromegaly and insulin resistance would result in improvement in insulin sensitivity and whether IGF-I had any additional insulin-sensitizing effects over and above those induced by its ability to suppress GH secretion. Five patients with active acromegaly were treated for 2 wk with a GH receptor antagonist. The GH receptor antagonist was effective, as IGF-I fell 65%, and mean GH values rose 42%. Mean fasting insulin fell from 39 ± 6 to 30 ± 7 μU/ml, and this was accompanied by a 9% decrease in fasting glucose. After treatment the insulin sensitivity index was 2.7 ± 1.0 × 10⁻⁴/min·μU/ml compared with a baseline value of 1.65 ± 0.8 × 10⁻⁴/min·μU/ml (P < 0.015). Subsequently, the subjects were treated with the receptor antagonist plus IGF-I/IGF-binding protein-3 given by sc injection (1 mg/kg daily). After 2 wk of the combined treatment, fasting insulin fell from 49 ± 9 to 29 ± 7 μU/ml, and fasting glucose fell by 14%. The insulin sensitivity index improved to 4.34 ± 1.3 × 10⁻⁴/min·μU/ml, which was significantly greater than the value obtained after treatment with the GH antagonist alone. Although only a limited number of subjects were studied, the results strongly suggest that IGF-I has insulin-sensitizing actions that are independent of its ability to suppress GH secretion. These findings necessitate further studies into the non-GH-related mechanism by which IGF-I enhances insulin sensitivity.