Selective cyclooxygenase-2 (COX-2) inhibitors have been found to induce anti-proliferative and apoptotic activity in many cancer cells. However, interaction between COX-2 inhibitors and other chemotherapeutic agents remains to be determined. We investigated the interactive effects of a selective COX-2 inhibitor, etodolac, in combination with 5-fluorouracil (5-FU) or SN-38 (active metabolite of irinotecan) on colon cancer cell lines, HT29 and SW620, in simultaneous and sequential administration schedules. Isobologram analysis demonstrated that etodolac in combination with 5-FU or SN-38 according to a simultaneous schedule resulted in only an additive effect; however, synergism was achieved in a sequential schedule. Apoptosis induction in both cell lines was also significantly increased after sequential treatment with etodolac followed by either 5-FU or SN-38 compared to that after simultaneous treatment with etodolac and either 5-FU or SN-38. Our study suggests apoptosis-inducing synergism resulted from administration of etodolac and either 5-FU or SN-38 sequentially, but not simultaneously.