Insulin-producing beta-cells were selectively absent from the islets of Langerhans in postmortem specimens from two patients with Wolfram's syndrome. In families with multiple cases of this syndrome, we found a very high concordance rate (r = .910, P less than .001) among siblings for age at onset of diabetes mellitus. Taken together with the lack of markers for an autoimmune process, these findings suggest that diabetes mellitus in this syndrome results from genetically programmed selective beta-cell death.