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Electroporation-based mono-gene therapy has received great interest in recent years but coadministration of different therapeutic genes for treatment of tumors has not been well explored. We hypothesize that electroporation is capable of delivering multiple genes that induce an additive or synergistic antitumor effect. To test this hypothesis, we used mice that were bearing SCCVII or TRAMP tumors. Established tumors with a diameter of 4–5 mm were injected with control plasmid DNA or plasmid DNA encoding B7.1, IL-12 or bothviaelectroporation. Tumor regression, CTL activity and the level of B7.1, IL-12 and Stat1 expression were determined in both wild-type mice and in mice with a knock-out of the Stat1 gene. Remarkably, a single coadministration of the plasmids that encoded IL-12 and B7.1 eradicated tumors in 80% of mice. The therapeutic effect was associated with high levels of endogenous B7.1 expression, activity of cytotoxic lymphocytes, and activation of Stat1. Both exogenous B7.1 and IL-12 were required for inducing a high level of Stat1 activation in tumors, which occurred through a mechanism that was independent of the host Stat1. Both stimulators were also required for inducing the strong cytotoxic lymphocyte activity and for increasing the level and extending the duration of endogenous B7.1 expression. We therefore propose a 2-signal stimulation model to explain the synergistic effect of the coadministration of IL-12 and B7.1 on the regression of the tumors.