The alteration of caveolin-1 (Cav-1) during carcinogenesis is of great interest and its over-expression in the tumor cell cytoplasm can predict a poor prognosis of renal cell carcinoma (RCC). However, whether the over-expression in RCC is associated with inherited polymorphism is not clear. In this hospital-based case-control study, the association of Cav-1 genotypes with RCC risk in a central Taiwanese population was investigated. Ninety-two patients with RCC and five hundred and eighty of age/gender-matched healthy controls were recruited and genotyped for six polymorphic sites at Cav-1, C521A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992). The results showed that there were statistically different distributions of the genotypic (P = 0.0170 and 0.0011) and allelic (P = 0.0033 and 0.0352) frequencies for the Cav-1 G14713A and T29107A polymorphisms among RCC patients and control subjects, respectively. As for the haplotype analysis, subjects carrying "GG/AT or GG/AA" at Cav-1 G14713A/T29107A showed a 2.06-fold increased odds ratio of RCC compared to those with GG/TT, while those of any other combinations were of unaltered odds ratios. In conclusion, this is the first report providing evidence showing that Cav-1 genotype is associated with RCC. The results showed that the G allele of the Cav-1 G14713A and the A allele of the Cav-1 T29107A are risky genetic factors for RCC susceptibility and the combinative GG/AT or GG/AA haplotype at Cav-1 G14713A/T29107A can serve as one of the RCC predictors for Taiwanese.