Recently, we have demonstrated a direct correlation among hyperglycaemia, vascular dysfunction and eNOS post-translational regulation in non non-obese diabetic mice (NOD). Here, we evaluate the impact of two ACE-inhibitors therapy, zofenopril and enalapril in NOD mice. Insulin-dependent diabetes mellitus (IDDM) development was monitored weekly through glycosuria measurement. Zofenopril and enalapril were dosed at 0.5 mg/kg/die orally. Animals were sacrificed at different points and aortas used for western blotting or for tissue bath experiments. Bovine aortic endothelial cells in high glucose medium are treated with zofenoprilat or enalaprilat. Cells and supernatant were utilised for western blot analysis and for nitrite/nitrate determination, respectively. In ex-vivo experiments chronic administration of both drugs restored PE-induced contraction but not Isop-induced vasodilatation, however only zofenopril reduced caveolin-1 expression. In vitro, both drugs inhibited caveolin-1 expression and increased NOx production. However, zofenopril caused inhibition of both parameters at a concentration 200 fold lower than enalalpril. In vivo, zofenopril delays the onset of diabetic conditions of about 50%, and ameliorates polyuria. In conclusion our data suggest that ACE-inhibitor therapy may be useful in IDDM, in particular sulphydrylated inhibitor would display a better efficacy especially if administered early on the development of diabetes.