Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has a pivotal role in normal and pathological angiogenesis. VEGF has a long 5' untranslated region harboring an open reading frame (ORF) initiated by a CUG codon that is in-frame with the VEGF coding region. The ORF translation leads to the expression of a long isoform termed L-VEGF that is extended by an additional 180 amino acids. In this communication, we provide evidence that L-VEGF is subjected to proteolytic cleavage leading to the detachment of the 180 aa extension from the VEGF moiety. Using immunofluorescence staining, we show that upon hypoxia this 180 aa extension translocates to the nuclei of expressing cells. Accordingly, immunohistochemical staining of both normal and tumor tissue samples demonstrated restricted nuclear localization of the ORF, which was correlated with cytoplasmic localization of VEGF. This suggests that the 180 aa ORF is involved in VEGF-mediated angiogenic processes.