The link between ERG rearrangement and PTEN (phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situ hybridization, we systematically validated the frequency and distribution of ERG and PTEN aberrations in a cohort of 73 benign prostate tissues, 59 high-grade prostatic intraepithelial neoplasia (HGPIN) foci, 281 localized prostate cancer and 47 androgen-independent metastatic prostate cancer patients. Overall, ERG rearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTEN deletion was identified in 9% (3/33) of HGPIN, 17% (42/251) of localized cancers and 54% (22/41) of metastases, of which 0%, 40% (17/42) and 45% (10/22) were homozygous, respectively. Concomitance of ERG rearrangement and PTEN deletion was observed in a subset of HGPIN. Significantly, association between PTEN deletion and ERG rearrangement was present both in localized cancers (P=0.0008) and metastases (P=0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTEN genomic deletion both in localized and metastatic cancer. Of note, ERG aberration, but not PTEN deletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERG status across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTEN deletion status across multiple sites. Collectively, our data support PTEN deletion as a late genetic event in human prostate cancer, presumably a 'second hit' after ERG rearrangement. PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression.