Proliferative retinopathies is the major cause of blindness in industrialized countries this is characterized by neuronal depolarization, calcium influx and oxidative stress. In the present study we have investigated the effects of the hypoxia-mimetic CoCl2 200mM in human retinal pigment epithelium (HRPE) cells. After treatment there was a strong induction of HIF1a, confirming that the experimental approach was an acceptable model for in-vitro hypoxia. The cells showed a significantly reduced viability, together with the increased expression of VEGF confirmed that the HRPE cells respond to the lost of oxygen by increasing cell death (apoptosis as shows by a dramatic increase in caspase 3 expression) and by trying to increase blood flow through the release of VEGF.These effects seem to be related to oxidative stress as the results parallel with an increased level of 8-iso PGF2 isoprostane, 4HNE protein adducts and ROS formation. The responses of the HRPE cells to the increased oxidative stress is the induction of NFkB activity as confirmed by immunohystochemistry analysis. The activation of the transcription factor NFkB could be also the trigger for the VEGF increased levels in cells exposed to hypoxia. The present results provide evidence of the possible mechanistic pathway involved in retinopathy, where the first step is the existence of and hypoxic event, which leads to increased oxidative stress and oxidized proteins that via the activation of NFkB stimulates the production of VEGF.In parallel, oxidative stress will consequently damage the cells with an increased mortality via the induction of apoptosis.