1. The impact of different genetic risk loads defined by HLA-DQB1 alleles on the autoimmune and clinical characteristics of 647 children and adolescents with recent-onset Type I diabetes was evaluated in a prospective population-based study. The subjects were divided into four groups based on HLA-DQB1 genotypes: DQB1*0302/0201 (high risk), *0302/x (moderate risk), *0201/y (low risk) and *z/z (decreased risk). 2. Close to two thirds (62.3%) of the subjects possessed a high or moderate risk genotype. A decreased frequency of positivity for islet cell antibodies (ICA) and insulin autoantibodies (IAA) (76.8% compared with 85.3%; P = 0.05, and 30.5% compared with 50.8%, P = 0.0006, respectively) but not of positivity for antibodies to the 65 kDa isoform of glutamate decarboxylase was observed in children with the DQB1*0201/y genotype compared with other children. Among ICA-negative subjects, those with the DQB1*0201/y genotype had higher serum C-peptide levels over the first 2 years after the diagnosis of Type I diabetes than those with other genotypes (P = 0.028). 3. Our data provide some evidence of HLA-DQB1-determined heterogeneity in the autoimmune and clinical characteristics of childhood Type I diabetes at the time of the clinical manifestation. This suggests differences between children with various HLA-DQB1 genotypes in the pace and/or intensity of the beta-cell destructive process leading to clinical Type I diabetes.