Ductal pancreatic adenocarcinoma is one of the commonest and most lethal cancers in the Western world. Unfortunately, recent advances in diagnostics, staging, and therapy in pancreatic carcinoma have not resulted in significant improvements in long-term survival. We have previously shown that adenovirus (Ad)-mediated coexpression of interleukin-12 (IL-12) and the costimulatory molecule B7.1 is extremely efficient in inducing regression of highly immunogenic transplanted and nontransplanted tumors. Here, we examined the antitumor efficacy of IL-12- and B7.1-based immunotherapy against a nonimmunogenic murine model of ductal pancreatic cancer. Compared with AdIL-12 treatment alone, single intratumoral injection of AdIL-12/B7.1 led to a prolonged immune response and mediated complete regression in 80% of treated animals. After rechallenge with parental tumor cells, 70% of cured mice remained tumor-free, suggesting that protective immunity had been induced. The antitumoral response was associated with upregulation of H-2K(b) and Abcb2 expression, whereas other components of the proteasome (Abcb3, Psmb9, and Psmb8) were not affected. These data indicate that upregulation of the antigen presentation machinery by AdIL-12/B7.1 may be a therapeutic rationale for nonimmunogenic, therapy-resistant pancreatic cancer.