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The increasing clinical incidence and host risk of open fracture-associated infections, as well as the reduced effectiveness of conventional antibiotics to treat such infections, have driven the development of new therapies for the prophylaxis of open fracture-associated infections. We investigated percutaneous supplementation of a natural cytokine (i.e. interleukin 12p70 or IL-12) at an open fracture site to reduce open fracture-associated infections. We also determined the efficacy of the combination therapy of IL-12 and conventional antibiotic therapy in the prophylaxis of open fracture-associated infections. An open femur fracture infection model was produced by direct inoculation of a clinical isolate of Staphylococcus aureus after creating a femur fracture using rats. The animals were assigned to one of four groups: no drug administration, percutaneous supplementation of IL-12, intraperitoneal administration of the antibiotic ampicillin, or percutaneous IL-12 in combination with intraperitoneal ampicillin. Animals were euthanized at post-operative days 6, 10, 14, and 21. Percutaneous IL-12 led to a reduction in infection at post-operative days 6 and 10. For the first time, exogenous IL-12 was found to have additive effects in the prevention of infection when combined with conventional treatment (i.e. antibiotic therapy). Combination therapy of ampicillin and IL-12 substantially reduced the infection rate at post-operative day 6 and also decreased the time needed for complete inhibition of infection. Therefore, exogenous IL-12, providing a mechanism of protection independent of antibiotic resistance, complements the routine use of antibiotics.