Death receptor-3 (DR3) plays controversial roles in cancer. Currently, DR3 is known to be a functional receptor of vascular endothelial growth inhibitor (VEGI). The role of DR3 in breast cancer remains unclear. The present study investigated DR3 expression in a clinical cohort of breast cancer patients and its role in breast cancer cells in vitro. The expression of DR3 was examined in a breast cancer cohort using quantitative PCR (Q-PCR) and immunohistochemistry (IHC) in comparison to the patients' data. In vitro function of DR3 was examined through the targeting of this molecule in MCF7 and MDA-MB-231 breast cancer cells using ribozyme transgene technology. Decreased DR3 expression was noted in breast cancer tissues compared to normal tissues and decreased expression of DR3 was generally associated with a poorer prognosis as well as a significantly shorter long-term survival (p=0.038). Targeting of DR3 in vitro in breast cancer cell lines resulted in impaired migratory rates compared to respective control cells. Collectively, these data suggest a complex role for DR3 in breast cancer development and progression.