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AIM: To investigate the role of SMYD3 in hepatocellular carcinoma (HCC) development and progression and to verify whether its regulation activity was through RIZ1 inactivation.METHODS: Expression of SMYD3 in HCC cell lines and tissues were measured; silencing of SMYD3 by RNA interference (RNAi) was effectuated, hepatoma cell proliferation, migration and apoptosis were tested, with RIZ1 CpG promoter methylation, and corresponding mRNA expression were investigated.RESULTS: SMYD3 over-expression in HCC was associated with RIZ1 hypermethylation and mRNA down-expression. Suppression of SMYD3 expression demethylated RIZ1 CpG promoter (P ＜ 0.01) and increased RIZ1 mRNA expression (P ＜ 0.01). Consequently, SMYD3down-expression with RIZ1 de-methylation strongly inhibited hepatoma cell growth (MTT inhibitory rates:Pgenesil-1-s1 60.95% ± 7.97%, Pgenesil-1-s2 72.14%± 9.68% vs Pgenesil-1-hk 6.89% ± 4.12%, P ＜ 0.01)and migration (Pgenesil-1-s1 4.24% ± 1.58%, Pgenesil-1-s1 4.87% ± 0.73% vs Pgenesil-1 19.03% ± 4.63%,Pgenesil-1-hk 19.95% ± 5.21%, P ＜ 0.01) and induced apoptosis (FCM subG1 phase Pgenesil-1-s1 19.07% ±1.78%, Pgenesil-1-s2 17.68% ± 2.36% vs Pgenesil-1 0.47% ± 0.12%, Pgenesil-1-hk 1.46% ± 0.28%,P ＜ 0.01. TUNEL-positive cells: Pgenesil-1-s1 40.24%± 5.18%, Pgenesil-1-s2 38.48% ± 4.65% vs Pgenesil-1 2.18% ± 1.34%, Pgenesil-1-hk 2.84% ± 1.22%,P ＜ 0.01) in HepG2 cells.CONCLUSION: These results demonstrate that SMYD3plays a critical role in the carcinogenesis and progression of HCC. The proliferation, migration induction and apoptosis inhibition activities of SMYD3 may be mediated through RZ1 CpG promoter hypermethylation.