The histone methyltransferase SET8 is regulated by microRNA-502 through the binding site in its 3'-untranslated region, and the rs16917496 polymorphism at the miR-502-binding site in the SET8 gene has been implicated in a number of cancer types. The rs16917496 polymorphism including CC, CT and TT genotypes was analyzed in patients with colorectal cancer; the CC genotype was identified to be independently associated with longer post-operative survival times using multivariate analysis (relative risk, 2.406; 95% confidence interval, 1.017-5.691; P=0.046). In addition, decreased SET8 expression was associated with the SET8 CC genotype and longer survival times for patients with colorectal cancer. The results of the present study indicated that miR-502 mediates SET8 expression at least partly by altering the binding affinity between miR-502 and SET8 so as to modify the colorectal cancer outcome. The results indicate that SET8 may be a novel target for colorectal cancer therapy.