Colorectal cancer (CRC) and hypodontia are frequent and different diseases with common genes are involved in their etiology. The objective of this study was to identify the association between AXIN2 rs2240308 with hypodontia and CRC.This study consisted of 50 individuals with hypodontia, 50 individuals with CRC, and 155 healthy individuals from Colombia. SNP genotyping assays of rs2240308 were performed and family history of cancer in individuals with hypodontia was documented. In silico analysis was implemented to define the genomic profile of the AXIN2 gene associated with CRC. Multivariate analysis, chi square, odd ratio tests, and R software were used for statistical analysis.AXIN2 rs2240308 showed association with CRC (OR = 5.4 CI: 2.7-10.4; p < 0.001) and with other familial cancer in individuals with hypodontia (p < 0.005 OR = 1.75, 95% CI: 1.22-6.91). In silico analysis showed that variations in AXIN2 found in CRC patients, were more frequently in earlier stages of tumor and patients who carry variations in the AXIN2 gene have a worse prognosis (p < 0.05). The association between AXIN2 rs2240308 with hypodontia was not significant.These results suggest that AXIN2 rs2240308 polymorphism is associated with CRC and AXIN2 could be a risk marker for predisposition and prognosis of CRC.