Abstract： Objective Renal papillary cell carcinoma(RPCC) has been historically regarded as a radio-resistant malignancy. However, the molecular mechanism underlying its radio-resistance is not well understood. Recently,STAT1, a transcription factor downstream of the IFN-signalling pathway, has been implicated in radioresistance. This study is to investigate the role of STAT1 in "radio-resistant RPCC". Methods The expression of STAT, in 137 human RPCC samples compared with 15 normal kidney tissues was examined by micrearray expression profiling using the Affymetrix HGU133 Plus 2.0 GeneChip oligonucleotide arrays. For in-vltro experiments, human RPCC cell line(SKRC-39), human fibroblast(CCL-116) and human Wiim's tumor cell line(CRL-1441) were used. Western blotting was performed to evaluate total and phosporylated STAT1 expression. RPCC cells were irradiated and compared to controls in clonogenic assays. STAT1 inhibition either with fludarabine or siRNA was done and their effects on radiation-induced cell survival were investigated. Results The STAT1 expression data shows that there was a significant increase in human RPCC when compared to normal kidney tissues (t=44.38,P=0.000). Similarly, the expression of STAT1 was higher in the RPCC cell line when compared to firbroblast and Wilm's tumor cell lines. STAT1 expression was inhibited by beth fludarabine and siRNA. Radiosensitivity in RPCC cell lines was enhanced by both fludarabine and siRNA induced STAT1 inhibition. Conclusions This is the first study reporting the over-expression of STAT1 in human RPCC tissues and human RPCC cell line. Radiesensitization of RPCC is observed via inhibition of STAT1 signaling by fludarabine and siRNA techniques. Our data suggests that STAT1, through IFN-signalling pathway , may play a key role in RPCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.