Autoantibodies against the insulin receptor are found in the serum of some patients with severe insulin resistance. The effects of one of these sera on insulin binding and on glucose transport and metabolism were investigated in the isolated mouse soleus muscle. Preincubation of muscles with the patient's serum resulted in an inhibition of subsequent 125I-insulin binding (half-maximal effect at 1:500 dilution) and in a two to three-fold stimulation of glucose transport and metabolism (half-maximal effect at 1:2000 dilution). The insulin-like effects were blocked by anti-human IgG, but not by anti-insulin antibodies. The magnitude of the serum effects on 2-deoxyglucose uptake and glycolysis was similar to that of insulin, but the effect on glycogen synthesis was smaller than that of insulin. It is suggested that the patient's serum and insulin promote glucose transport and glycolysis through a common pathway, but act differently on glycogen synthesis.