To study the association of histocompatibility (HLA) genes in black persons with juvenile-onset diabetes, we determined HLA-A, HLA-B, HLA-C and HLA-DR specificities in 40 black Americans with this disease and in 67 unaffected black Americans. Marked increases in the frequencies of HLA-DRw3 and HLA-DRw4 were found in the patients as compared with the unaffected persons: DRw3 was found in 72.5 per cent of patients versus 29.9 per cent of unaffected persons and DRw4 in 72.5 per cent versus 25.4 per cent (corrected P values each <0.0007). DRw2 was not found in any of the patients but was present in 26.9 per cent of unaffected persons (P corrected <0.035). There is thus a negative correlation between this specificity and juvenile-onset diabetes. By contrast, no meaningful differences were found in the frequencies of A, B, or C locus antigens. Studies in white persons with juvenile-onset diabetes have suggested that the reported HLA-B associations are due to HLA-D region specificities, and our results also support the premise that D region specificities are the primary associations with juvenile-onset diabetes. (N Engl J Med 301:810–812, 1979) INSULIN-dependent, juvenile-onset diabetes mellitus in whites is associated with increased frequencies of several histocompatibility (HLA) antigens, including B8, B15, B18, Cw3, Dw3, DRw3, Dw4 and DRw4.1 2 3 4 5 6 7 The number and strength of these antigen associations have varied according to the geographic location of the patients and have reflected the genetic heterogeneity of whites in different parts of the world. The strongest associations have been with Dw3/DRw3 and B15, and it is assumed that the relatively weaker associations with B8, B18, Cw3 and perhaps Dw4/DRw4 are due to linkage disequilibrium with Dw3 and B15. Current hypotheses thus propose that at least two.