Genetic variants may affect the interactions between microRNAs (miRNAs/miRs) and their target genes by modulating their binding affinity or by creating, or destroying a miRNA-binding site. SET domain containing (lysine methyltransferase) 8 (SET8) is the sole lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20, and is associated with tumor growth, invasion and metastasis. In the present study, the rs16917496 polymorphism within the miR-502 binding site of the SET8 mRNA 3' untranslated region (3'UTR) in patients with clear cell renal cell carcinoma (ccRCC) and healthy controls was genotyped. The SET8 CC genotype was associated with a decreased ccRCC risk compared with the CT [P= 0.003; odds ratio (OR)= 0.318; 95% confidence interval (CI), 0.146-0.691], TT (P= 0.011; OR= 0.402; 95% CI, 0.197-0.819) and CT+TT (P= 0.004; OR= 0.370; 95% CI, 0.186-0.736) genotypes. The SET8 CC genotype was associated with reduced SET8 expression based on immunostaining of ccRCC tissue. Low SET8 protein levels were negatively associated with tumor-node-metastasis staging in patients with ccRCC according to the size of tumor and lymph node metastases. SET8-knockdown inhibited renal carcinoma 786-O cell proliferation, migration and invasion. c-Myc and matrix metalloproteinase-7 mRNA expression were downregulated upon SET8-knockdown in renal carcinoma 786-O cells. These data indicated that SET8 may be a functional tumor promoter and that its activation, which is partially regulated by changing the miR-502 and SET8 3'UTR binding affinity, may serve an important role in ccRCC development.