The human retinoic acid receptor alpha (hRAR alpha) exhibits cell-specific transcriptional activity. Previously, it was shown that in the absence of hormone the wild-type receptor is a transcriptional silencer in L cells, whereas it lacks silencing function and is a weak activator in CV1 cells. Addition of hormone leads to a further increase in transactivation in CV1 cells. Thus, the retinoic acid response mediated by RAR alpha is weak in these cells. It was shown that the CV1-specific effect is due to the receptor C terminus. We show, that the failure of silencing by RAR is not due to a general lack of corepressors in CV1 cells, since the silencing domain of RAR is functionally active and exhibits active repression in these cells. Furthermore, we show that the conserved AF2/tau c activation function of RAR is responsible for the cell-specific inhibition of silencing. Thereby, the CV1 cell specificity was abolished by replacing AF2/tau c of RAR with the corresponding sequence of the thyroid hormone receptor. Thus, we find a new role of the C-terminal conserved activation function AF2/tau c in that, specifically, the RAR AF2/tau c-sequence is able to prevent silencing of RAR in a cell-specific manner. In addition, we show that the inhibitory effect of AF2/tau c in CV1 cells can be overcome by expression of the corepressor SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), but not by that of N-CoR (nuclear receptor corepressor). The expression of these two corepressors, however, had no measurable effect on RAR-mediated silencing in L cells. Thus, the expression of a corepressor can lead to a dramatic increase of hormonal response in a cell-specific manner.