Insulin receptor autophosphorylation is the earliest recognizable event in insulin action subsequent to insulin binding. To determine if the postbinding hepatic insulin resistance of nonketotic diabetes mellitus could reside in an inability of insulin to stimulate insulin receptor autophosphorylation, we evaluated the ability of insulin to stimulate 32P incorporation into the beta subunit of lectin-purified rat liver plasma membrane insulin receptors. The data indicate that both the absolute plasma membrane insulin receptor autophosphorylation in response to insulin as well as the insulin dose-response relationship for autophosphorylation are normal in diabetic animals when expressed per microgram of protein or per unit of binding activity. The previous data from our laboratory indicates that hepatic insulin resistance in non-ketotic streptozotocin-induced diabetes mellitus is present despite normal to increased insulin binding, is selective, is reversible with insulin treatment and involves an inability of insulin to stimulate the release of the putative mediator of insulin action. We conclude, therefore, that the hepatic insulin resistance of nonketotic diabetes mellitus resides distal to insulin receptor binding and autophosphorylation and is reflected in metabolic events at or near the plasma membrane which may include the generation or release of the putative mediator of insulin action.