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We have demonstrated that the rat sodium iodide symporter (rNIS) and ¹³¹I can effectively induce growth arrest of human prostate tumor xenografts [Mitrofanova, E., Unfer, R., Vahanian, N., Daniels, W., Roberson, E., Seregina, T., Seth, P., and Link, C. (2004). Rat sodium iodide symporter (rNIS) for radioiodide therapy of cancer. Clin. Cancer Res. 10, 6969–6976]. In that study the average size of tumors established in athymic nude mice was 200 ± 50 mm³ when treated. Testing under more rigorous and extreme in vitro conditions will better evaluate the ability of an anticancer approach to induce tumor regression or killing capacity in preclinical studies. In this work the ability of the rNIS and ¹³¹I system to inhibit the growth of relatively large (about 800 mm³ when treated with ¹³¹I) and rapidly growing colon tumors in an animal model was examined. in vitro experiments demonstrated that transduction of human colon cancer cells with Ad-rNIS resulted in a 100- to 150-fold increase in ¹²⁵I uptake compared with nontransduced cells. Western blot analysis revealed robust expression of rNIS protein in cells 72–120 hr posttransduction with Ad-rNIS. Immunocytochemical analysis demonstrated that intracellular localization of rNIS-specific staining was observed mainly in plasma membranes of cells. in vitro studies revealed an immediate inhibition of growth of rapidly expanding tumors after radioiodine injection in the rNIS and ¹³¹I treatment group of mice. Twenty-seven percent of experimental mice survived more than 30 days (p = 0.019), whereas control groups had only 7% survival over 30 days. This is the first report demonstrating that rat NIS and ¹³¹I can effectively induce growth arrest of relatively large tumors in an animal model.