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Interferon (IFN)-α is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-α, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-α on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth-inhibitory effect of IFN-α. Suppression of SOCS3 expression in 786-O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN-α. An in vivo study indicated that co-administration of SOCS3-targeted siRNA promoted IFN-α-induced cell death and growth suppression in 786-O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3-induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells. (Cancer Sci 2011; 102: 57–63)