Prostate cancer is one of the most common carcinomas among adult males. Recently, genome-wide association studies (GWAS) have identified several susceptibility genes of prostate cancer. However, these single locus results can only explain a small proportion of the genetic etiology. In order to understand how multiple genetic variants may contribute to the penetrance of prostate cancer, we conducted a genome-wide SNP-SNP interaction study in four populations, involving 5,269 cases and 5,289 controls. We exhaustively evaluated all pairs of SNP-SNP interactions for 661,658 SNPs that were consensus in all four groups, and then performed a meta-analysis to combine the results. We found multiple variants within region 7p21.3 and 18p11.22 significantly interacted with each other and reached genome-wide significance levels. The most significant epistasis was between rs1105255 (intergenic, near RBSG3) and rs651431 (intergenic, near VAPA) (p = 1.4 x 10(-14)). Notably, VAPA was identified to be the protein-coding transcripts as PTEN competing endogenous RNA in prostate cancer. And PTEN is a critical tumor suppressor gene frequently altered in cancers. In addition, 7p21.3 involves several pseudogenes, whose parental genes are cancer-related. Recently, growing evidence strongly suggests they are of multifaceted involvements in the pathogenesis of cancer. Multiple regulatory elements were found within 7p21.3 and 18p11.22, indicating the variants might regulate the nearby genes and confer risk of disease. Additionally, we also found several other significant epistasis, most of which were near or in cancer-related genes. Drug target enrichment analysis suggested genes in top epistasis significantly overlapped with target genes of FDA-approved drugs for treatment of prostate cancer.