We have evaluated the effects of metformin administration on erythrocyte insulin receptors in 21 subjects: 5 normal weight subjects, 5 obese non diabetics, 5 insulin-dependent diabetics (Type I) and 6 obese non insulin-dependent (Type II) diabetics. Plasma glucose, plasma insulin and erythrocyte insulin receptors were studied after 15 days of metformin (850 mg, t.d.) or placebo administered in a double blind random order. Maximum specific insulin binding to erythrocytes increased after metformin in the normals (p less than 0.01), in the obese non diabetics (p less than 0.01) and in the obese Type 2 diabetics (p less than 0.005), but not in Type I diabetics. Scatchard analysis showed that the receptor number per cell increased by 37% in the normals, by 17% in the obese non diabetics and by 182% in Type 2 diabetics. Receptor affinity increased in obese subjects but did not increase in normals and in diabetics. Only in Type II diabetics was there a significant decrease in plasma glucose. Metformin, thus, increased binding in normals by moderately increasing the capacity of cell receptors, in obese non diabetics by increasing the affinity, whereas in obese Type II diabetics it dramatically increases receptor capacity. This is consistent with the fact that metformin has a hypoglycaemic effect mainly in Type II diabetics, but not in non diabetics (whether obese or not), and could be due to a direct effect on the cell membrane.