Abstract: Caspase-8 (CASP8) plays a key role in apoptosis. We examined by genotyping whether the -652 six-nucleotide insertion-deletion (6N ins/del) polymorphism in the CASP8 promoter region associated with prostate cancer risk in a hospital-based cohort of 406 Chinese prostate cancer patients and 408 age-matched cancer-free controls. Additionally,23 prostate cancer tissues were analyzed for CASP8 mRNA expression. We found a significantly decreased prostate cancer risk for the 6N ins/del genotype adjusted odds ratio (OR)=0.68; 95% confidence interval (CI)=0.51-0.92 and del/del genotype (OR=0.34; 95% CI=0.19-0.63) compared with the ins/ins genotype. The 6N del allele was associated dose-dependently with decreased prostate cancer risk (Ptrend = 0.001). RT-PCR showed that individuals with the 6N del allele had lower CASP8 mRNA levels than those with the ins/ins genotype (P =0.024). These findings suggested that the CASP8 -652 6N ins/del polymorphism may affect the susceptibility to prostate cancer and reduce prostate cancer risk among Chinese men.