A variety of retinal disease lead to a decrease in the sensitivity of the S (blue) cone pathways. To determine the possible sites and mechanisms of this loss we compared the sensitivities of an S (blue/pi-1) and an M (green/pi-4) cone pathway in patients with retinal diseases that differ as to their primary locus of sensitivity loss. The sensitivities of an S and an M cone pathway were assessed in patients with retinitis pigmentosa, insulin-dependent diabetes mellitus and open-angle glaucoma using Stiles two-color increment threshold technique. A greater loss in sensitivity of an S than an M cone pathway was found for all three disease groups; however, the diabetic patients showed a more selective loss. The results suggest that multiple sites are involved and that the combined effects of metabolic abnormalities and hypoxia contribute to the selective loss.