OBJECTIVES: p18 is a haploinsufficient tumor suppressor. Once cell is damaged or uncontrolled, the tumor suppressor goes into cytoplasm and phosphorylates with ataxia telangiectasia mutated (ATM), resulting in inhibition of cell cycle progression and induction of p53-mediated apoptosis of the cells. Deficiency or loss-of-function mutations are frequently observed in various human cancer cell lines and tumor specimens. We hypothesize that cell permeable (CP-) p18 fused to Macromolecule Transduction Domain (MTD) could be delivered into and inhibit tumorigenesis in vivo by regulating cell cycle progression of cancer cells. METHODS: We evaluated to the expression of anti-cell cycle progression molecules and pro-cell cycle progression factors by western blot analysis to in vitro study. In addition, we evaluated to in vivo test of CP-p18 as a anti-cell cycle progression agent. RESULTS: CP-p18 tested in cancer cells in vitro showed efficient intracellular delivery and increased anti-cell cycle progression molecules such as phospho-p53, phospho-ATM and p21. In contrast, phosphorylation of MEK, ERK and Rb involved in cell cycle progression were significantly decreased. In addition, CP-p18 treatment also induced apoptosis by arresting cell cycle. In the tumor implanted mouse model, intraperitoneal (IP), intravenous (IV) and intratumor (IT) administration of CP-p18 were dramatically induced the reduction of tumor growth and eventually removed the solid tumor completely. CONCLUSIONS: These results strongly suggest that CP-18 could be a effective protein-based biotherapeutic agent to treat various human cancers.