Retinoids have been shown to inhibit the growth of many human tumor cells. Although the exact molecular mechanism of retinoid-mediated growth suppression remains known, the importance of the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been in established a number of tumor cell models. We wanted to determine if modulation of RAR/RXR function would alter the retinoid sensitivity of oral squamous carcinoma cells (SCCs). Growth of SCCs was significantly suppressed by treatment with either all-trans retinoic acid (RA) or the synthetic, conformationally restricted RAR-gamma-selective retinoids SR 11254 and SR 11389. In contrast, stable oral SCC clones that constitutively overexpressed the mouse dominant negative mutant, RAR-beta (R269Q), were shown to exhibit reduced RAR/RXR transcriptional transactivation function and reduced sensitivity to growth inhibition by RA, SR 11254 and SR 11389. Likewise, the RAR-gamma antagonist SR 11253 was found to block the ability of SR 11254 and SR 11389 to inhibit SCC growth. These results indicate that modulation of RAR function through the use of either an RAR-gamma-selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCCs to retinoids.