The histopathology of capillary-free areas in diabetic retinopathy was studied in 27 lesions from 12 human donor eyes. Localised capillary-free areas were identified on casts of the retinal vascular system, and on subsequent histological sections of these areas the casted vessels acted as points of reference to accurately combine the histological appearance of the retina with the vascular morphology as seen on the cast. All studies lesions showed inner retinal changes with loss of ganglion cells, attenutation of the inner nuclear layer and hyalinization of the retinal capillary network. In 21 of the studied lesions a homogeneous eosinophil substance was seen accumulated between the photoreceptor outer segments and the retinal pigment epithelium corresponding to the areas with inner retinal changes. The findings may help explain the blocking of choroidal fluorescence in capillary-free areas as seen on fluorescein angiograms in diabetic retinopathy. The study suggests future guidelines for further illumination of the pathophysiology of proliferative diabetic retinopathy.