OBJECTIVE To elucidate the significance of clinical and immunogenic heterogeneity in Japanese children with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS Serial changes in the prevalence of islet cell antibodies (ICAs) and in ICA titer were monitored for 10 years after diagnosis in 34 IDDM children, 17 with abrupt onset and 17 with slow onset, whose durations of disease were > 5 years. RESULTS In slow-onset IDDM children, enough β-cell function was maintained in the early phase of the disease within 2 years after diagnosis. There was a high prevalence of ICAs in children with both forms of IDDM at the time of diagnosis (abrupt onset 94% slow onset 82%). However, the decline in the frequency of ICAs in slow-onset IDDM seemed less marked than in abrupt-onset IDDM after a duration of ≥ 1 year (47 vs. 82%, 1–3 years; 24 vs. 47%, 3–5 years; 24 vs. 47%, 5–7 years; 18 vs. 53%, 7–10 years, P < 0.05). In terms of changes in ICA titer, abrupt-onset IDDM children initially had high ICA levels of 160–320 Juvenile Diabetes Foundation units (JDF U), but these titers decreased rapidly after the 1st year. On the other hand, slow-onset IDDM children tended to continue to be ICA+ for a relatively long period with low titers of 20–40 JDF U. Among 12 children who remained ICA+ for > 5 years, slow onset was noted in 67% while abrupt onset was seen in only 33%. CONCLUSIONS From these results, we speculated that changes in ICA titer reflect the slow autoimmune destruction of pancreatic β-cells. It may be probable that immunogenic factors as well as environmental factors could affect the clinical features in the early phase of IDDM in children.