Secreted frizzled-related protein 1 (SFRP1) is a candidate tumor suppressor gene located at 8p11.2 and antagonizes the Wnt signaling pathway. Epigenetic inactivation of SFRP1 by methylation of its promoter CpG island has recently been reported in several types of cancers. In the present study, we examined the expression and methylation status of SFRP1 in renal cell carcinoma (RCC). Three RCC cell lines were tested and none expressed the SFRP1 transcript. Bisulfite sequencing of the SFRP1 promoter and treatment of the RCC cell lines with 5-aza-2'-deoxycytidine and/or trichostatin A revealed the association between SFRP1 expression and promoter hypermethylation. Methylation-specific PCR detected hypermethylation in 26/57 (45.6%) conventional RCC cases and 2/8 (25%) papillary RCC cases. Quantitative real-time PCR showed >3-fold decrease of SFRP1 expression in 33/34 (97.1%) conventional RCC cases. Microsatellite analysis showed loss of heterozygosity at the SFRP1 locus (D8S1180) in only 3/28 (10.7%) conventional RCC cases. The present findings indicate that methylation-associated silencing of SFRP1 frequently occurs in RCC and plays a pivotal role in early carcinogenesis. However, previous immunohistochemical studies on beta-catenin have suggested that activation of the canonical Wnt pathway through beta-catenin stabilization is infrequent in RCC. Thus, further basic studies are required to elucidate how the loss of SFRP1 activity contributes to the Wnt and other signaling pathways in RCC.