Cancer metastasis accounts for a significant proportion of morbidity and mortality in patients. Effective means of treating disseminated disease remains elusive. The purpose of this study was to determine whether genetically modified endothelial cells (GMEC) can selectively target and deliver recombinant therapeutic molecules to sites of tumor metastases. Following the establishment of lung metastases of 4T1 mammary tumor in mice, intravenously (i.v.) administered, lacZ transgene-expressing endothelial cells (lacZ-GMEC) accumulated at the tumor sites. An average of 32% and 90% of the pulmonary metastases were X-gal stained following one and three tail vein injections of 10(5) lacZ-GMEC, respectively. The linear pattern of X-gal staining seen within the tumor sites and the histological appearance of the tumor vasculature were consistent with the incorporation of lacZ-GMEC into blood vessels. In C57Bl/6 mice harboring lung metastases of melanoma, the administration of three sequential i.v. injections of 10(5) endothelial cells expressing a human interleukin 2 transgene abrogated the tumor metastases and prolonged survival of the animals. These results demonstrate that i.v.-administered GMEC can selectively accumulate, survive, and stably express exogenous genes at multiple tumor sites. These findings support a role for i.v.-administered GMEC as a potential therapeutic strategy for the systemic treatment of cancer metastases.