The prognosis of pancreatic cancer with metastases or recurrence is quite poor. Chemotherapy has not resulted in a significant survival benefit; median survival is 3-6 months. Various chemotherapeutic agents have been evaluated and the standard chemotherapy of pancreatic cancer is gemcitabine. The response rate, however, is low at 13%. Thalidomide and celecoxib have different mechanisms of action and activity in various malignant tumors. Both have been evaluated and shown to demonstrate activity against solid tumors. Thalidomide decreased the stability of TNF-mRNA and COX-2 mRNA. COX-2 is a bifunctional enzyme possessing both cyclooxygenase and peroxidase activities. Although celecoxib inhibits PG biosynthesis, most do not affect the peroxidase activity of COX, which can generate proximate carcinogens. Because thalidomide does not completely inhibit COX-2 expression or PG biosynthesis, a therapeutic strategy combining celecoxib with thalidomide might be more effective than using either agent alone. Differences in the mechanism of action of gemcitabine and irinotecan suggest that a change of gemcitabine to irinotecan could provide clinically efficacious outcomes. In order to accomplish new treatment strategies, we have been using thalidomide, celecoxib and irinotecan in low-doses. We believe this combination represents a viable treatment for patients of pancreatic cancer with recurrence or metastases.