Insulinlike growth factor I (IGF-I) has been suggested to play a role in the pathogenesis of proliferative diabetic retinopathy (PDR). We determined IGF-I levels in subjects in a large population-based study of 928 people with diabetes diagnosed at 30 yr of age or older. PDR was found in 15.7% of the insulin-using group (n = 517) and in 2.8% of those not using insulin (n = 397). The mean serum level of IGF-I was 208 micrograms/L in individuals using insulin and 222 micrograms/L in those not using insulin, both significantly lower than in a nondiabetic comparison group (278 micrograms/L, P less than 0.0001). Logistic regression analysis was used to examine the relationship between IGF-I and PDR while controlling for other factors associated with the presence of PDR. After controlling for duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of proteinuria, and age at diagnosis, higher levels of IGF-I were significantly associated with an increased frequency of PDR (P = 0.025) in the group using insulin. In individuals not using insulin, higher levels of IGF-I were associated with an increased frequency of PDR or moderate non-PDR (P = 0.08). These data suggest that higher IGF-I levels may be a risk factor for the development of severe retinopathy in people with diabetes diagnosed at 30 yr of age or older.