Gene transfer of potent immunostimulatory cytokines such as interleukin-12 (IL-12) is a potential treatment for advanced cancer. Different vectors and IL-12 modifications have been developed to avoid side effects associated with high serum levels of the cytokine, while preserving its antitumor properties. Here we have evaluated two alternative strategies using the Syrian hamster as a model for pancreatic cancer metastatic to the liver. Local administration of an oncolytic adenovirus (OAV) expressing a single-chain version of IL-12 caused transient, very intense elevations of IL-12 in serum, resulting in severe toxicity at sub-therapeutic doses. Anchoring IL-12 to the membrane of infected cells by fusion with the transmembrane domain of CD4 reduced systemic exposure to IL-12 and increased the tolerance to the OAV. However, only a modest increase in the therapeutic range was achieved because antitumor potency was also reduced. In contrast, systemic administration of a helper-dependent adenoviral vector (HDAd) equipped with a Mifepristone-inducible expression system allowed sustained and controlled IL-12 production from the liver. This treatment was well tolerated and inhibited the progression of hepatic metastases. We conclude that HDAds are safer than OAVs for the delivery of IL-12, and are promising vectors for immunogene therapy approaches against pancreatic cancer.