We examined retinal de novo histamine synthesis mediated by retinal histidine decarboxylase in normal and streptozotocin-diabetic male, Sprague Dawley rats that were diabetic for 21 days. We also examined effects of insulin and alpha-hydrazinohistidine (alpha HH) treatments on retinal histamine synthesis in this diabetic model. alpha HH is a specific inhibitor of histidine decarboxylase. Results indicate that the retina contains an active histidine decarboxylase enzyme system, and that in streptozotocin diabetes retinal histamine synthesis is increased 197%. Both insulin and alpha HH independently reverse and normalize retinal histamine synthesis. These data thus indicate that the retinal inducible histamine pool is increased in experimental diabetes, and that insulin is an important modulator of retinal histamine metabolism. This newly described retinal metabolic alteration may be one factor responsible for increased retinal vascular permeability in diabetic retinopathy.