We analyzed the risk of developing insulin-dependent diabetes mellitus (IDDM) in 411 siblings of patients with IDDM. We found that siblings who had a positive test for antibodies against islet cells (ICA) at the time of diagnosis of the index case had a higher risk of developing IDDM than did those who had negative tests. However, of the ten siblings who developed IDDM, only four were positive at the initial testing. The period of time elapsing from a negative test at screening to a positive test at diagnosis varied but was less than one year in one child. Two of the ten siblings who developed IDDM had negative tests both at screening and at diagnosis. Amongst siblings who were negative at the initial screening, those in whom the index case was diagnosed at a young age had a higher risk of developing IDDM than did those in whom the index case was diagnosed at an older age. The age of the sibling at the time of screening, the sex of the sibling, and a positive family history (one which includes in addition to the index case one or more first-degree relatives with IDDM) did not confer increased risk. Our data suggest that screening for ICA will have to be done often and will have to be continued into adult life in order to identify the 70-80% of diabetics who will be positive at some time in the evolution of their disease.