The Runt-related transcription factors (RUNX), mitogen-activated protein kinase (MAPK) 1 and eukaryotic translation initiation factor 4E (eIF4E) are potentially involved in tumorigenesis. We evaluated genetic variation in RUNX1 (40 tagSNPs), RUNX2 (19 tagSNPs), RUNX3 (9 tagSNPs), MAPK1 (6 tagSNPs), eIF4E (3 tagSNPs), eIF4EBP2 (2 tagSNP) and eIF4EBP3 (2 tagSNPs) to determine associations with colorectal cancer (CRC). We used data from population-based studies (colon cancer n = 1555 cases, 1956 controls; rectal cancer n = 754 cases, 959 controls with complete genotype data). Four statistically significant tagSNPs were identified with colon cancer and three tagSNPs were identified with rectal cancer. Whereas the independent risk estimates for each of the tagSNPs ranged from 1.21 to 1.52, the combined risk was greater than additive for any of the three combined high-risk genotypes {combined risk range 1.98 [95% confidence interval (CI) 1.45, 2.70] for eIF4E, RUNX1 and RUNX3 to 3.32 [95% CI 1.34, 8.23] for eIF43, RUNX2 and RUNX3}. For rectal cancer, the strongest association was detected for the combined genotype of RUNX1 and RUNX3 (odds ratio 1.87 95% CI 1.22, 2.87). Associations with specific molecular tumor phenotypes showed consistent and strong associations for CIMP+/MSI+ tumors where the risk estimates were consistently >10-fold and lower confidence bounds were over 3.00 for high-risk genotypes defined by RUNX1, RUNX2 and RUNX3. For CIMP+/KRAS2-mutated colon tumors, the combined risk for high-risk genotypes of RUNX2, eIF4E and RUNX1 was 7.47 (95% CI 1.58, 35.3). Although the associations need confirmation, the findings and their internal consistency underline the importance of genetic variation in these genes for the etiology of CRC.