Polyethylene glycol (PEG) has been shown to repair cell membranes thus inhibiting free radical production in in vitro and in vivo models. We hypothesized that PEG and new developed organic nitrate forms of PEG (PEG-NO) could repair endothelium dysfunction in ischemia reperfusion (I/R) in the hamster cheek pouch visualized by intravital fluorescent microscopy. After treatments, we evaluated diameter, RBC velocity and flow in arterioles as well as lipid peroxides in the systemic blood, perfused capillary length, vascular permeability, leukocyte adhesion and von-Willebrand-factor (vWF) amount in the blood after I/R. A control group was treated with PEG₅₀₀₀ or PEG₁₀₀₀₀ Da MW, while three groups were treated with PG1 (1 NO molecule covalently bound to PEG, MW 5170 Da), PG8 (8 NO molecules, MW 11860 Da) and PG16 (16 NO molecules, MW 14060 Da). All the animals received 0.5 mg/0.5 ml. Lipid peroxides increased at 5 and 15 min reperfusion, while the diameter, RBC velocity and blood flow decreased in arterioles in I/R. Vascular permeability, leukocyte adhesion and vWF increased significantly. PEG and PG1 attenuated lipid peroxides, vasoconstriction during reperfusion, decreased leukocyte adhesion and vascular permeability. PG8 maintained lipid peroxides at normal levels, increased arteriolar diameter, flow and PCL, and decreased vWF level and leukocyte adhesion (p < 0.05). PG16 was less effective than PG1 and PG8. In conclusion, PEG-NO is a promising compound that protects microvascular perfusion by normalizing the balance between NO level and excessive production of free radicals in endothelial cells during I/R.