Diabetic retinopathy can result in apoptotic cell death of retinal neurons, as well as significant visual loss. It is further known that insulin-like growth factor (IGF) levels are reduced in diabetes and that IGF-I can prevent cell death in many cell types. In this study, we tested the hypothesis that systemic treatment with IGF-I could inhibit death of neuroretinal cells in diabetic rats by examining the expression of proapoptotic markers. In diabetic rat retina, the number of TUNEL-immunoreactive cells increased approximately sixfold in the photoreceptor layer (P<.001) and eightfold in the inner nuclear layer (INL; P<.001); phospho-Akt (p-Akt; Thr 308) immunoreactivity increased eightfold in the ganglion cell layer (GCL; P<.001) and threefold in the INL (P<.01). Subcutaneous IGF-I treatment significantly reduced the number of TUNEL (P<.001) and p-Akt immunoreactive retinal cells (P<.05) in diabetic rats approximately to the level of the nondiabetic group. Qualitative results showed that caspase-3 and BAD immunoreactivities were also elevated in diabetes and reduced in IGF-I-treated animals. Elevated TUNEL and p-Akt immunoreactivities were localized to distinct cell layers in the retina of diabetic rats. Early intervention with systemic IGF-I reduced the presence of proapoptotic markers indicative of neuroretinal cell death, despite ongoing hyperglycemia and weight loss. The eye is a special sensory organ, and these data show that cell loss in the nervous system, even in uncontrolled diabetes, can be prevented by IGF-I administration.