In a prospective investigation of the prediabetic period before onset of type 1 (insulin-dependent) diabetes, HLA genotypes were determined in 582 healthy parents and siblings of 160 affected children. Islet cell antibody was sought by both the conventional (ICA-IgG) and the complement fixation (CF-ICA) techniques during regular prospective observation over a mean period of 2.0 years. 4 siblings and 2 parents became diabetic; the interval before detection of any biochemical abnormality exceeded a year in 4 of these (range 3-30 months), and in all cases ICA-IgG was positive from the outset, CF-ICA being positive in 5. These observations suggest that the initiation of pathogenesis may precede the abrupt clinical onset of diabetes by several years, even in children. This has important implications, both for research and for possible future prophylaxis.