HLA types and blood glucose control were investigated in 127 insulin-dependent diabetics with different grades of severity of retinopathy. The means of all afternoon clinic blood glucose levels from the diagnosis of diabetes were 9.9 ± 2.1 mmol/L for patients with no retinopathy, 11.8 ± 2.1 mmol/L for patients with background retinopathy, and 12.4 ± 2.1 mmol/L for patients with proliferative retinopathy (P < 0.0001). HLA-DR4 was present in 61 of 87 patients (70%) with background or proliferative retinopathy and 21 of 39 (54%) with no retinopathy. The frequency of HLA-DR4 was lowest in patients with no retinopathy despite “poor control” (mean blood glucose ≥ 11.5 mmol/L) and highest in those who had developed retinopathy despite “good control;” the frequencies of HLA-DR2 showed the reverse pattern. Mantel-Haenszel tests were used to calculate the odds ratios for the presence of retinopathy associated with “poor control” and with HLA-DR4, since each modified the effect of the other. The odds ratio for retinopathy associated with “poor control” was 6.7 (P < 0.0001). The odds ratio with HLA-DR4 was 3.7 (P < 0.005). When both risk factors were present, the odds ratio increased to 33.3 (P < 0.0001). Genetically determined factors appear to influence susceptibility to retinopathy in insulin-dependent diabetics.