The conversion of glucose to sorbitol by aldose reductase (AR) and its subsequent intracellular accumulation have been implicated in the pathogenesis of diabetic cataracts. There is also evidence linking AR activity with renal capillary basement membrane thickening in galactosemic rats, suggesting a possible role in diabetic retinopathy. In this study, we explored one feature of this issue by examining diabetic and nondiabetic eyes for immunoreactive AR. AR was immunohistochemically undetectable in the retinal pigment epithelia (RPE) and neural retinas of nondiabetic human eyes. Weak, focal staining for AR was present unilaterally in the RPE of 1 of 11 diabetic patients without pathologic ocular findings and in 43% of diabetic patients with mild ocular findings. Retinal positivity was found (unilaterally) in only 2 of 19 individuals from either of these mildly affected groups. Fifty-five percent of patients with background retinopathy demonstrated AR positivity in the RPE, and half of these expressed AR in the RPE of both eyes. Of the individuals with proliferative diabetic retinopathy, 87.5% showed bilateral staining in the RPE. Retinal positivity was present in 36% of background retinopathy and 75% of proliferative retinopathy cases, demonstrating a positive correlation between AR expression and the severity of the disorder. In weakly staining retinas, only the ganglion cell bodies, nerve fibers, and Muller cells were positive, whereas in intensely staining cases, virtually the entire retina, except for the rod outer segments, was positive. Eyes from patients who had had diabetes ≤ 6 yr were negative for AR, but those from long-term-diabetic patients (14-45 yr) manifested positivity. These data suggest that enhanced expression of AR may play a role in the development of diabetic retinopathy.