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The Diabetes Control and Complications Trial (DCCT) demonstrated that a regimen of intensive therapy aimed at maintaining near-normal blood glucose values markedly reduces the risks of development or progression of retinopathy and other complications of insulin-dependent diabetes mellitus (IDDM) when compared with a conventional treatment regimen. This report presents an epidemiological assessment of the association between levels of glycemic exposure (HbA1c) before and during the DCCT with the risk of retinopathy progression within each treatment group. The initial level of HbA1c observed at eligibility screening as an index of pre-DCCT glycemia and the duration of IDDM on entry were the dominant baseline predictors of the risk of progression. The shorter the duration of IDDM on entry, the greater were the benefits of intensive therapy. In each treatment group, the mean HbA1c during the trial was the dominant predictor of retinopathy progression, and the risk gradients were similar in the two groups; a 10% lower HbA1c (e.g., 8 vs. 7.2%) is associated with a 43% lower risk in the intensive group and a 45% lower risk in the conventional group. These risk gradients applied over the observed range of HbA1c values and were unaffected by adjustment for other covariates. Over the range of HbA1c achieved by DCCT intensive therapy, there does not appear to be a level of glycemia below which the risks of retinopathy progression are eliminated. The change in risk over time, however, differed significantly between the treatment groups, the risk increasing with time in the study in the conventional group but remaining relatively constant in the intensive group. The risks were compounded by a multiplicative effect of the level of HbA1c with the duration of exposure (time in study). Total glycemic exposure was the dominant factor associated with the risk of retinopathy progression. When examined simultaneously within each treatment group, each of the components of pre-DCCT glycemic exposure (screening HbA1c value and IDDM duration) and glycemic exposure during the DCCT (mean HbA1c, time in study, and their interaction) were significantly associated with risk of retinopathy progression. Similar results also apply to other retinopathic, nephropathic, and neuropathic outcomes. The recommendation of the DCCT remains that intensive therapy with the goal of achieving near-normal glycemia should be implemented as early as possible in as many IDDM patients as is safely possible.