Insulin autoantibodies (IAA) are frequently found in newly diagnosed untreated insulin-dependent diabetics. We evaluated whether the insulin antibody response over the first year of treatment with insulin was different in individuals with IAA v those without IAA. One hundred five previously untreated type I diabetics were randomly assigned to treatment with either pure porcine or mixed bovine/porcine insulin. Twenty-one in each group had detectable IAA at diagnosis. Percent binding rose in all patients after commencing insulin therapy and was significantly greater in those with IAA at diagnosis irrespective of the type of insulin administered. The elevated binding in the IAA positive patients at all time points was equivalent to the binding that could be attributed to the insulin autoantibodies. Two different mechanisms could explain this greater insulin antibody binding during insulin therapy in the IAA positive patients. First, there may be summation of binding due to insulin autoantibodies and binding due to insulin antibodies formed in response to the exogenous insulin. Alternatively, the insulin antibodies formed in response to exogenous insulin could replace the IAA, with those individuals positive for IAA at diagnosis having a proportionately greater antibody response to injected insulin. Irrespective of the mechanism, patients with IAA at diagnosis develop higher insulin antibody measurements when subsequently treated with exogenous insulin.