To identify risk factors for diabetic retinopathy in insulin-dependent diabetes mellitus (IDDM), we studied the relationships among residual beta-cell function, human leukocyte antigen (HLA), long-term glycemic control, and development of diabetic retinopathy in 128 IDDM patients. Residual beta-cell function was assessed by serum C-peptide immunoreactivity (CPR) response to a 100-g oral glucose load (delta CPR). The patients were stratified into three groups: those with delta CPR of < 0.033 nmol/l (group 1, n = 50), those with delta CPR of 0.033-0.1 nmol/l (group 2, n = 38), and those with delta CPR of > 0.1 nmol/l (group 3, n = 40). The cumulative incidence rate of background retinopathy was higher in the order of groups 1, 2, and 3 (P = 0.032). Group 1 progressed to preproliferative retinopathy at an earlier stage than did groups 2 and 3 combined (P = 0.028). Further progression to proliferative retinopathy tended to be earlier in group 1 than in groups 2 and 3 combined (P = 0.083). The mean HbA1c value rose from 9.01 +/- 1.06% (mean +/- SD) in group 3 to 9.75 +/- 0.79% in group 2 to 10.48 +/- 1.12% in group 1 (P < 0.0001). In group 1, 89.6% of the patients had HLA-A24, whereas 50 and 43.6% of the patients had this antigen in groups 2 and 3 respectively (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)