TNFerade is a replication incompetent adenovector designed to express human TNFalpha under control of the Egr-1 radiation and chemotherapy enhanced promoter, and is currently in Phase II/III clinical testing. Data from Phase I clinical testing of TNFerade in a limited set of melanoma patients suggested the potential to impact distal metastases following intratumoral injections of TNFerade. These clinical observations and the multiple potential mechanisms of TNFerade led us to hypothesize local treatment with TNFerade + radiation may impact metastatic disease. We explored this hypothesis in preclinical models using the spontaneously metastatic, syngeneic B16F10 murine melanoma model. Established subcutaneous B16F10 tumors were treated with intratumoral injections of TNFerade and localized 2 Gy fractionated radiation therapy, modeling the clinical treatment regimen. Following 10-14 days of treatment, mice were evaluated for metastases development in the iliac and axillary lymph nodes. Comparisons of metastatic burden to control groups indicated TNFerade +/- radiation suppressed the formation of metastases in the lymph nodes. Additional experiments in TNF receptor knockout mice, where the only possible effects are on tumor cells containing the TNFalpha receptor, indicate TNFerade's local and distal activities are critically dependent on a host-mediated response. These data provide direct preclinical evidence local therapy of a solid tumor with TNFerade can also reduce metastatic disease, in addition to effects on the treated lesion. Furthermore, our finding of a host dependant response(s) for TNFerade at both the treated tumor and on lymph node metastases suggest the potential for broad activity independent of tumor histology.