Aurora B kinase (AURKB) and epidermal growth factor receptor 1 (EGFR) belong to serine/threonine and tyrosine kinase family of proteins. Both these kinases are found to overexpress in a large number of epithelial cancers, including hormonal refractory prostate cancer. In this communication, we present evidence for down-regulated expression of AURKB and EGFR, either alone or in combination, in prostate cancer cells. The results show that AURKB and EGFR were efficiently down-regulated in a dose-dependent manner. AURKB and EGFR siRNA in combination have shown enhanced therapeutic effect by inhibiting PC3 cell proliferation and inducing apoptosis in vitro, whereas androgen-dependent cancer cells LNCaP remain unaffected correlating the endogenous expression levels. Knockdown of AURKB and EGFR individually resulted in inhibition of prostate tumor growth in athymic nude mice and their combined knockdown resulted in tumor regression in which 40% of the treated mice were found to be tumor free, implicating the potential therapeutic benefits of AURKB-EGFR combination therapy.