Vascular endothelial growth factor (VEGF) plays a pivotal role in diabetic retinopathy (DR) and hypertension has been identified as an independent risk factor for DR. The aim of the present study was to: (1) explore whether beta-adrenergic blockers influence retinal VEGF expression; (2) determine the effect of angiotensin-converting enzyme inhibitors (ACEI) on retinal VEGF expression independently of their anti-hypertensive actions; and (3) investigate the correlation between retinal VEGF expression and changes in retinal capillary basement membrane thickness (BMT). Streptozotocin-induced diabetic rats and control animals were assigned at random to receive the beta-adrenergic blocker propranolol, the ACEI fosenopril sodium, or vehicle for 24 weeks. Enzyme linked immunosorbent assay, immunohistochemistry, Western blot, and real-time reverse transcription-polymerase chain reaction were used to assess VEGF protein and mRNA expression. Computer-assisted morphometric measurements of transmission electron microscopy photographs were performed to evaluate BMT. Vitreous fluid and retinal VEGF protein and retinal VEGF mRNA expression were significantly higher in diabetic rats than in control rats, with a significant reduction in fosenopril sodium-treated diabetic rats (p<0.01). There was no significant difference in VEGF levels in diabetic rats and propranolol-treated diabetic rats (p>0.05), but there was a significant difference in VEGF protein and mRNA expression in propranolol-treated diabetic rats and fosenopril sodium-treated diabetic rats (p<0.01) without any significant difference in systolic blood pressure in the latter two groups (p>0.05). There was a significant correlation between the level of retinal VEGF expression and changes in retinal BMT (p<0.01). These findings suggest that the effect of ACEI on retinal VEGF expression is independent of their anti-hypertensive actions and that ACEI could offer particular benefits beyond blood pressure reduction in the treatment of DR with or without hypertension. beta-adrenergic blockers had no influence on retinal VEGF expression in normal or diabetic rats.