The malignant human keratinocyte line SCC4 provides a model system to study the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses retinoid induction of the tissue transglutaminase gene (TGM2). The current work explores the nature of TCDD suppression of retinoid action to determine whether it is gene specific, whether it is retinoid receptor isoform-dependent, and whether it requires close proximity of retinoid and TCDD response elements. First, two other retinoid-inducible genes were identified in SCC4 by microarray screening whose induction was unaffected by TCDD, clearly demonstrating the gene specificity of TCDD suppression. Second, the receptor isoform dependence of retinoid responsiveness in SCC4 was tested. TGM2 was found to be inducible by an RARalpha-specific but not by an RARgamma-selective agonist. A lack of responsiveness to RARgamma agonists was found to be characteristic of SCC4, however, inasmuch as transcription driven by a retinoid response element in transfections was also stimulated only by the alpha-specific agonist in these cells. Because SCC4 lacks expression of RARbeta, the gene specificity evidently was not attributable to differential TCDD targeting of retinoid receptor isoforms. Finally, the proximal 5 kb of the TGM2 promoter was found to be retinoid responsive in stable transfections, but the induction was not suppressed by TCDD. These results indicate that the suppressive action of TCDD occurs indirectly and through a separate DNA site likely located outside the 5-kb region, not by direct interference with retinoid action or at retinoid response elements.