Islet cell antibodies (ICA)-IgG are the serological marker of type 1 diabetes, an organ-specific autoimmune disease. A proportion of patients also have thyro-gastric autoimmunity, implying a broader humoral autoreactivity in these cases. In order to determine whether this is also reflected within islet cell antibodies (ICA) we examined the ICA-IgG subclass distribution in type 1 diabetic patients with or without associated thyro-gastric autoantibodies. ICA-IgG subclasses were detected by two-step indirect immunofluorescence, using monoclonal antibodies against the four IgG subclasses, in sera from 51 patients with type 1 diabetes and detectable ICA; 31 had no other antibodies (group 1) and 20 had at least one associated thyroid and/or gastric autoantibody (group 2). Our results show that ICA are polyclonal and invariably IgG1. In 48% of patients with type 1 diabetes without associated thyro-gastric autoantibodies, ICA were restricted to IgG1 only. Conversely, only 10% of those with thyro-gastric antibodies had ICA-IgG1 only (P < 0.02), and a larger ICA-IgG subclass recruitment was observed in these patients (P = 0.002). These findings provide evidence of heterogeneity within ICA at the IgG subclass level, with a broader clonal recruitment within this specificity in individuals displaying features of multiple organ autoimmunity. These results support the hypothesis of heterogeneity within the pathogenetic process leading to type 1 diabetes.