PTEN (phosphatase and tensin homolog deleted on chromosome 10) functions as a major tumor suppressor gene and is frequently deleted in different types of tumors including prostate cancer (PCa). It was hypothesized that germ-line genetic changes of PTEN affect susceptibility to PCa. Both common (with a minor allele frequency 5%) and rare (with a minor allele frequency <5%) germ-line variants of PTEN were comprehensively evaluated. A total of 15 germ-line variants were identified by re-sequencing the PTEN gene, including 5' untranslated region, all nine exons, exon-intron junctions and 3' untranslated region, in 188 probands of hereditary prostate cancer (HPC) families recruited from Johns Hopkins Hospital. Two microsatellite markers surrounding PTEN were used to test the co-segregation of 10 rare variants, which may give rise to highly penetrance in HPC. Two common single nucleotide polymorphisms (SNPs) were evaluated in the 188 HPC families using a family-based association study approach. To study low penetrant SNPs in PCa susceptibility, 33 SNPs covering PTEN were selected from the whole genome-wide association studies (GWAS) from our available case-control studies in Sweden (Cancer of the Prostate in Sweden (CAPS)) and the publicly available cancer genetic markers of susceptibility (CGEMS) study. Germ-line copy-number variations (CNVs) in PTEN were assessed in CAPS. Co-segregation of germ-line variants and PCa was not observed among HPC families and no significant differences in the allele frequencies were observed in sporadic cases and controls, aggressive and non-aggressive PCa (P>0.05). These results suggest that germ-line variants in PTEN do not have an important role in PCa susceptibility.