The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of -emitting ¹³¹I in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance ¹³¹I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) / produced marked NIS induction and selective stimulation of RAR, RAR, or retinoid X receptor (RXR), produced more modest induction. Maximal NIS induction was seen with 9-cis RA and AGN190168, a RAR / agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC₅₀ of tRA for NIS stimulation to 7%, such that 10^-7 M tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of ¹³¹I greater than 10^-6 M tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 days) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis RA/Dex. The addition of Dex reduced the effective dose of retinoid, and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of ¹³¹I after combination treatment.