Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.