Abstract: Objective To explore the role of ubiquitin-like with PHD and ring finger domain 1 (UHRF1) in the invasion and metastasis of gastric cancer (GC) cells. Methods We examined UHRF1 expression in two pairs of highly metastatic and lowly metastatic GC cell lines by RT-PCR and Western blot. Western blot and in vivo metastasis assays were conducted to measure the migration and invasion abilities of GC cells after UHRF1 expression was altered by siRNA or vector. Then methylation specific PCR and Western blot were performed to detect the methylation status and the expression of p16^INK4A and RB1. Results UHRF1 expression was markedly higher in highly metastatic GC cells compared with their counterparts. Down-regulation of UHRF1 expression suppressed the invasion and metastasis of GC cells, and increased p16^INK4A and RB1 genes expression via promoter demethylation. Up-regulation of UHRF1 expression showed the opposite results. Conclusion UHRF1 could promote the invasion and metastasis of GC cells via regulating p16^INK4A and RB1 methylation. UHRF1 may become a new target for early warning and treatment of GC metastasis.