Oxaliplatin, the first line chemotherapeutic of colon cancer, induces damage to tumors via induction of apoptosis. PUMA (p53 up-regulate modulator of apoptosis) is an important pro apoptotic member of Bcl-2 family and regulated mainly by p53. Here we investigated the role of PUMA in oxalipaltin induced apoptosis and the potential mechanism. We showed that oxaliplatin induced PUMA expressioninatime anddose dependentmannerandsuppres sion of PUMA expression by stable transfecting anti sense PUMA plasmid decreased oxa liplatin induced apoptosis in colon cancer cells. By abrogating the function of p53, we further demonstrated that the induction was p53 independent. We also found that oxali platin could inactivate ERK and suppression of ERK activity by its specific inhibitor (PD98059), and dominant negative plasmid (DN MEK1) enhanced the oxaliplatin induced PUMA expression and apoptosis in a p53 independent manner. Taken together, our data suggest that PUMA plays an important role in oxaliplatin induced apoptosis and the induction could be both p53 dependent and p53 independent. Moreover, PUMA expression and apoptosis in oxaliplatin treated colon cancer cells could be regulated partly by ERK inactivation. Identification of the molecular components involved in regulating the cellular sensitivity to oxaliplatin may provide potential targets for development of novel compounds that maybe useful in enhancement of oxaliplatin cytotoxicity in p53 deficient colon cancer.