OBJECTIVE: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. DESIGN AND METHODS: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. RESULTS: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. CONCLUSION: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.