Ornithine decarboxylase (ODC), the key enzyme of poly-amine biosynthesis, has paradoxical roles in apoptosis. Our published papers show overexpression of ODC pre-vents the apoptosis induced by many cytotoxic drugs. Thapsigargin (TG) is an inhibitor of the sarcoplasmic/en-doplasmic reticulum (ER) Ca2+ ATPase (SERCA) pumps and causes ER stress-induced apoptosis. We used ODC overexpressing cell lines to examine whether overexpres-sion of ODC inhibits TG-induced apoptosis. Our results indicated overexpression of ODC attenuated TG-induced apoptosis. Overexpression of ODC blocked procaspse-4 cleavage and phosphorylation of protein kinase-like ER-resident kinase (PERK), triggered by TG. It also attenuated the increase in CAAT/enhancer binding protein homolo-gous protein (CHOP). Cells with overexpressed ODC had greater Bcl-2 expression. Overexpression of ODC pre-served the expression of Bcl-2, inhibited the increase in Bak and stabilized mitochondrial membrane potential without the influences of TG. Cytochrome c release and downstream caspase activation were blocked. That is, overexpression of ODC inhibits the mitochondria-medi-ated apoptotic pathway, induced by TG. Finally, overex-pression of ODC maintains the protein and mRNA expres-sion of SERCA. In conclusion, overexpression of ODC suppresses TG-induced apoptosis by blocking caspase-4 activation and PERK phosphorylation, attenuating CHOP expression and inhibiting the mitochondria-mediated apoptotic pathway.