The role of susceptibility low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear, but may involve in some cases multiple alleles at multiple loci.To evaluate the association of gene-gene and gene-environment interactions with PCa.One hundred three subjects with biopsy proven PCa were studied, using a case-only design. All were interrogated about smoking habits. Polymorphisms for Glutathione-S-transferase (GS7) and Cytochrome P4501A1 (CYP1A1), were measured in DNA extracted from peripheral lymphocytes, using a restriction fragment length polymorphism analysis.Our findings suggest that gene-gene interactions between GSTT1 and CYP1A1 high risk genotypes were positive modifiers and had a high predictive value for the presence of PCa, compared with non-susceptibility genotypes. The interaction between susceptibility genotypes and smoking did not modify the risk for PCa.Gene-gene interactions may play a role modulating the susceptibility to PCa in a proportion of affected individuals.