The immunogenicity of human insulin (Novo, Monotard, Actrapid) or pork monocomponent (MC) insulin (Monotard, Actrapid) was studied in 102 HLA-DR-typed patients with newly diagnosed insulin-dependent diabetes mellitus (type I diabetes). After 6 mo of treatment, IgG-insulin antibodies were found in only 14% of the patients receiving homologous MC insulins, but in 29% of the patients on heterologous MC insulins. IgG-insulin antibody titers were significantly lower in patients treated with human insulin compared with diabetic patients who received the corresponding pork MC insulin preparations from the onset of their disease. The previously reported strong influence of immunogenetic factors in determining the magnitude of the anti-insulin immune response was supported by the findings obtained in the pork MC insulin-treated diabetic individuals. Incidence of circulating immune complexes was 14% and 5% after 3 and 6 mo, respectively, of treatment with human insulin, which is considerably lower than previously reported in patients using heterologous non-monocomponent insulin preparations.