<b><i>Objective:</i></b> We investigated the association of the hedgehog pathway with nuclear factor (NF)-κB and clinical outcomes in pancreatic cancer patients. <b><i>Methods:</i></b> We analyzed tissue samples for the expression of NF-κB (RelA/p65), sonic hedgehog (Shh) and glioma-associated oncogene homolog 1 (Gli1) by immunohistochemistry and investigated their expression in association with clinical outcomes. <b><i>Results:</i></b> Eighty-one patients with pancreatic cancer were investigated. Expression of Shh and nuclear expression of Gli1 and NF-κB were found in 63 of 66 (96%), 28 of 68 (41%) and 22 of 68 cases (32%), respectively. Nuclear Gli1 expression was closely associated with nuclear expression of NF-κB (p < 0.001). Patients with nuclear Gli1 had significantly worse prognoses than those without (median survival 7.9 vs. 13.9 months; p = 0.009). Similarly, patients with nuclear expression of NF-κB had shorter overall survival than those with negative or cytoplasmic expression of NF-κB (median survival 5.5 vs. 13.9 months; p < 0.001). Shh expression had no prognostic significance. In the multivariate analysis, NF-κB nuclear expression was closely associated with unfavorable overall survival (p = 0.02). <b><i>Conclusion:</i></b> Our results indicate that nuclear expression of Gli1 or NF-κB is a strong predictor of poor prognosis in pancreatic cancer. Additional investigation of the biologic significance of this association is warranted.