Evading apoptosis is a hallmark of pancreatic cancer. In pancreatic cancer models, chemotherapy down-regulates the antiapoptotic protein cellular FLICE inhibitory protein (c-FLIP), which renders cells sensitive to apoptosis. Currently, the relevance of c-FLIP expression as a biomarker in pancreatic cancer is unknown, and here we assessed the prognostic significance of the c-FLIP expression status in a large cohort of pancreatic cancer patients with clinical follow-up. Cellular FLICE inhibitory protein expression levels were determined by immunohistochemistry in 120 surgically resected ductal pancreatic adenocarcinomas. Survival analysis by c-FLIP status was compared with established clinicopathologic biomarkers as well as Ki-67 and cyclooxygenase 2 expression levels as 2 other established independent prognostic biomarkers in pancreatic cancer. Of 120 tumors, 111 (91%) were c-FLIP positive, whereas 9 (9%) were completely c-FLIP negative. Cyclooxygenase 2 was positive in 59 cases (52%), and Ki-67 was positive in more than 10% of tumor cells in 51 cases (44%). Univariate and multivariate survival analysis (correcting for stage, grade, and proliferation index) showed that c-FLIP is an independent prognostic factor. Specifically, c-FLIP negativity identifies 9% of patients with a highly aggressive disease course (P = 0.0001). Cellular FLICE inhibitory protein expression status is a valuable prognostic biomarker in pancreatic cancer.