The relationship between HLA antigens and juvenile-onset diabetes mellitus was examined. Tissue typing for HLA antigens was carried out in 77 control subjects and in 133 individuals from 29 families, each of which contained one or more patients with juvenile-onset diabetes. A significant increase in the frequency of B18 antigen was found in the juvenile-onset index cases. In these index cases, the frequency of HLA antigens B8 and B15 was increased and the frequency of B7 and B12 was decreased, but these findings were not significantly different from those in the control subjects. Two examples of recombinations were noted among the 29 families, and in both instances the recombinations were present in the index case. In this selected population of diabetic patients and their first-degree relatives, there were three siblings (6%) who had juvenile-onset diabetes mellitus. This frequency of diabetes in siblings is much more than would be expected in individuals of the same age group. Two nondiabetic siblings had haplotypes identical to those of a diabetic sibling. These nondiabetic siblings may represent prediabetic individuals. The most frequent haplotype noted in diabetic patients and their first-degree relatives was A1, B8, which was present in approximately 25% of the index cases and first-degree relatives.