BACKGROUND The study was carried out to evaluate the correlation between blood-retinal barrier (BRB) permeability and the development of diabetic retinopathy (DR) and to assess the metabolic and clinical factors related to DR over a 4-year period by means of vitreous fluorophotometry (VF). METHODS Thirty-five type I diabetics with no retinopathy, age 7-21 years (mean 14.32 +/- 2.1 years) were enrolled in this longitudinal study. Two visits included standard ophthalmological examination, fluorescein angiography and VF were performed, on entry into the study and 4 years later. The following risk factors in DR were analyzed: age, duration of diabetes, blood pressure, cholesterol, triglycerides, fasting blood glucose levels, glycosylated hemoglobin (HbA1c), insulin dose/kg body weight (IDBW), fructosamine and albuminuria. To estimate the BRB permeability we adopted the vitreous penetration ratio transmittance (VPRt) value. RESULTS At 4-year follow-up the mean VPRt had significantly increased. During that time 13 patients developed DR and their final mean VPRt was significantly higher than that in non-DR patients. Additionally, the initial mean VPRt was higher but not significantly so, in patients that later developed DR than in non-DR subjects. A constant linear correlation was found between VPRt and duration of diabetes, HbA1c and microalbuminuria. CONCLUSIONS VF is a quantitative method that could measure and predict the breakdown of the BRB before angiographic retinopathy in type I diabetics. The major clinical and metabolic factors related to alterations in the BRB are duration of diabetes, HbA1c and microalbuminuria.