Colorectal cancer (CRC) is one of the most common malignant tumors, and its high rates of recurrence and metastasis are the important causes of treatment failure in CRC. Therefore, the development of valuable molecular markers to accurately predict the prognosis of CRC patients is vital. In the present study, we determined the expression of Cullin1 (Cul1) and c-Myc in a CRC tissue microarray containing 470 cancer and corresponding normal tissues by immunohistochemistry. We found that Cul1 and c-Myc expression was significantly upregulated in the CRC cancer tissues compared with that noted in the adjacent non-cancer tissues. High Cul1 expression in cancer tissues was associated with depth of invasion (P=0.005), lymph node metastasis (P=0.001) and TNM stage (P=0.015). High c-Myc expression in cancer tissues was significantly positively association with age (P=0.004), depth of invasion (P<0.001), lymph node metastasis (P<0.001) and TNM stage (P<0.001). Multivariate Cox regression analysis revealed that Cul1 or c-Myc expression was an independent and unfavorable prognostic factor for CRC patients [hazard ratio (HR), 0.749, 95% confidence interval (CI), 0.563-0.996, P<0.05; and HR, 0.384, 95% CI, 0.257-0.472, P<0.001, respectively]. Furthermore, Cul1 and c-Myc exhibited synergistic potential for the prediction of CRC prognosis, and the patients with low expression of both Cul1 and c-Myc had a favorable survival outcome (P<0.001).