The effects of 17-beta-oestradiol (E2) and progesterone (P) on insulin sensitivity were determined in oophorectomized (OVX) rats by the euglycaemic hyperinsulinaemic clamp technique combined with measurements of insulin-stimulated 2-deoxy-D-glucose (2-DOG) transport and glycogen synthesis in white and red parts of the gastrocnemius, the extensor digitorum longus and soleus muscles as well as in the liver (only glycogen synthesis). OVX was followed by insulin resistance in the clamp measurements. This was paralleled by a decreased insulin-stimulated content of 2-DOG in muscles, an index of glucose transport. Glycogen synthesis in muscle was also decreased, although to less extent. E2, alone or in combination with P, restored this to values of intact controls, while P alone was followed by insulin resistance. Liver glycogen synthesis was also decreased by OVX but this required combination of E2 and P to be fully restored. It was concluded that particularly E2 plays an important role in the maintenance of normal insulin sensitivity while P alone seems to be followed by insulin resistance, both effects apparently mainly by regulation of glucose uptake in muscle. E2 + P may be of importance for maintenance of normal glycogen synthesis in the liver.