Dysregulation of cellular metabolism is associated with multiple diseases including cancer. Polyamines are organic cations shown to control gene expression at the transcriptional, post-transcriptional, and translational level. The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is associated with normal and neoplastic growth. A single nucleotide polymorphism (SNP, rs2302615, SNP +316 nucleotides 3' of the transcriptional start site) in the ODC1 gene has been found to be both functional and prognostic for risk of colorectal carcinogenesis. A comprehensive investigation of genetic variability in ODC1 gene was performed. We confirmed frequencies of 12 SNPs occurring in participants of a clinical cancer prevention trial. We identified haplotypes accounting for over 90% of the genetic diversity in the ODC1 gene. Mechanistically, we addressed two of them, which account for more than half of the participants in the clinical trial. Two ODC1 intron 1 SNPs, rs2302616 (SNP +263 nucleotides 3' of the transcriptional start site) and rs2302615, were found to be associated with disease processes. Both of them predicted metachronous adenoma and response to agents targeting the polyamine pathway in participants of the clinical trial. The rs2302616 functionally modulate a DNA G-quadruplex structure and predicted the ODC1 rate-limiting product putrescine by genotype. Both SNPs cooperate to modulate ODC1 transcriptional activity involving both a G-quadruplex structure and Sp1 binding site at rs2302616, and rs2302615 flanked MYC-binding E-boxes. Haplotype analysis, using both these SNPs, might provide better discrimination of both disease prognosis and treatment prediction in cancer chemoprevention clinical trials.