Abnormal antibody responses to insulin in diabetic patients have been associated with syndromes of insulin hypersensitivity and abnormal insulin pharmacokinetics. In this study, we evaluated total and IgG subclass antibody responses to insulin in 70 diabetic subjects on insulin distributed into five clinical groups, and in two control groups using ELISAs with CDC/WHO recommended monoclonal antibodies. As expected, levels of total IgG insulin antibody were greater in diabetic patients treated with insulin than in the control group of diabetic patients on oral agents or nondiabetic controls. Insulin antibody responses of the IgG2 subclass were negligible to absent in all groups. Adult diabetic patients on insulin without complications and those with insulin associated anaphylaxis had mean values of IgG1, IgG3, and IgG4 insulin antibodies no different from those of controls. Patients with local hypersensitivity had elevated IgG1 responses. Type I diabetic patients had elevated IgG3 responses. A group of Type II diabetic patients selected for high levels of total IgG insulin antibodies had elevated levels of IgG1, IgG3, and IgG4 antibody responses. Thus, the IgG subclass response to insulin primarily involves IgG subclasses 1, 3, and 4 and varies with the type of diabetes and complications of insulin therapy.