The incidence of hepatobiliary cancers is increasing and no standard therapy currently exists. Gemcitabine is an active drug in this disease. Previous studies suggest that the combination of gemcitabine and irinotecan is active with reasonable toxicity profiles in pancreatic and hepatobiliary cancers. COX-2 induction and overexpression have been documented in biliary dysplasia and biliary malignancies. We report on a case series of the efficacy and toxicity of gemcitabine plus irinotecan plus celecoxib in patients with advanced biliary cancer. The treatment consisted of gemcitabine 1000 mg/m given intravenously on days 1 and 8, irinotecan 100 mg/m given intravenously on days 1 and 8, and celecoxib 400 mg orally twice daily every 21 days. Six patients were enrolled, one was ineligible, therefore data were examined on the five remaining patients. One patient had a complete response, one had a partial response, two had stable disease, and one received one cycle of treatment and decided on surgery hence could not be assessed. The treatment was well tolerated with one grade 4 adverse event of thrombocytopenia. In conclusion, the combination of gemcitabine, irinotecan, and celecoxib appears to be well tolerated with some activity against biliary cancer. Further studies using this combination are warranted.