We describe the design of the MIDIA study and present serial islet autoantibody data from 3months of age in the 526 first enrolled children from the general population carrying the type 1 diabetes high-risk HLA-DRB1*0401-DQA1*03-DQB1*0302/DRB1*0301-DQA1*05-DQB1*02 genotype. Blood samples were obtained from children at ages 3, 6, 9 and 12months and annually thereafter to a median age of 12months. Autoantibodies to insulin, glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured with radiobinding assays. About 25,000 general population newborns were genotyped, and among 526 children with the high-risk HLA genotype, 2104 samples were assayed. Fourteen children were positive in at least two consecutive samples, including 12 who were positive for ≥2 autoantibodies at least once, of which five developed type 1 diabetes at median age 15.3months. Seven of 14 persistently positive children seroconverted before 9months, including two before 6months of age. The estimated cumulative probability of multiple autoantibody positivity at 5years was 7.3% (95% confidence interval: 3.5–12.4%). Thus, persistent islet autoimmunity is not uncommon in the first year of life in children from the general population carrying the high-risk HLA genotype, and may develop as early as at 6months of age.