The renal cell carcinoma (RCC) is a rare condition, accounting for only 3% of all adult malignancies although constituting 90% of kidney cancers. The tumor is immunogenic and the host immune system may modulate the clinical course of the disease. It has been reported that genetic polymorphisms in the interleukin-4-receptor alpha gene are associated with risk and prognosis in RCCs. The present study is aimed at analyzing the presence and significance of the interleukin-4-receptor alpha Ile50Val and Gln576Arg polymorphisms in a group of RCC patients from South India. PCR-RFLP analysis was performed on genomic DNA isolated from blood samples and the genotypes deduced. A significant association was found between the IL4 R alpha Val/Val genotype and increased risk of RCC (OR: 3.45, CI: 1.15-10.38, P: 0.04). The Val/Val genotype was also found to be significantly associated with increased risk in individuals below 54 years (OR: 5.79, CI: 1.33-25.07 P: 0.03) of age and in females (OR: 7.47, CI: 1.4-39.84, P: 0.03). However, no significant association was observed with the Gln576Arg polymorphism. Stratified analysis based on the genotypes and the stage of tumor revealed no significant association. Thus, the present study indicates that IL4Ralpha could be a candidate gene for assessing the risk of RCC.