We have evaluated the role played by HLA antigens in the control of humoral response to exogenous insulin in a sample of Sicilian insulin-dependent diabetes mellitus patients. The results demonstrate that HLA-DR1-positive patients show the highest mean values of insulin antibody, whereas HLA-B18,DR3-positive patients show the lowest. Thus, present observations show that HLA-DR1- and HLA-DR3-linked genes do play opposite roles in the humoral immune response to an exogenous protein, i.e. injected insulin. These results might be consistent with the findings concerning the mechanisms involved in the resistance and/or susceptibility to immunological diseases. In this regard, the fact that no immunological spontaneous disorder has been shown to be associated with HLA-DR1, whereas several have been shown to be associated with HLA-DR3, is intriguing.