Background: Recent evidence suggests that the Wnt and Notch signaling pathways are involved in colon cancer progression and tumor recurrence. There is substantial germline genetic variability in these pathways, including single nucleotide polymorphisms (SNPs). SNPs may alter transcription, translation or splicing, thereby causing inter-individual differences in a patient’s tumor recurrence capacity and chemoresistance. We hypothesized that SNPs analyzed in a comprehensive panel of Wnt and Notch pathway genes predict clinical outcome in patients with colon cancer. Methods: A total of 815 patients with stage II and III colon cancer treated at the Medical University of Graz were included in this retrospective study. FFPE tissue specimens from normal tissue adjacent to the tumor samples were available from 599 patients. 18 SNPs in Wnt and Notch pathway genes (SFRP, DKK2, DKK3, Axin2, APC, MYC, TCF7L2 and NOTCH-2) were determined by 5’-exonuclease assay (TaqMan). The primary endpoint of the study was disease-free survival (DFS). Results: The homozygous mutant variant of AXIN2 rs2240308 G>A was associated with a significantly increased median DFS (HR 0.638, 95% CI 0.432-0.942, p=0.024) in univariate analysis. Patients carrying at least one G allele in AXIN2 rs2240308 G>A showed a median DFS of 114 months. In contrast, patients with homozygous A/A showed a median DFS of 133 months. After Cox proportional hazards model adjustment for known prognostic markers this result remained significant (HR 0.671, 95% CI 0.453-0.992, p=0.046). Conclusions: To the best of our knowledge, this is the first study identifying a common genetic variant in AXIN2 as an independent prognostic marker in stage II and III colon cancer. Larger prospective trials are warranted to confirm these findings.