Recently, a non-DNA binding protein, class II transactivator (CIITA), has been shown to be required for constitutive and IFN-γ-inducible class II MHC transcription. The cytokine TGF-β inhibits IFN-γ-induced class II MHC expression at the transcriptional level. In this study, we provide evidence that TGF-β blocks IFN-γ-induced CIITA mRNA accumulation. TGF-β down-regulates class II MHC and CIITA mRNA accumulation in human astroglioma and fibrosarcoma cell lines, but TGF-β does not destabilize the CIITA message, suggesting an effect at the transcriptional level. In cells that stably overexpressed CIITA, leading to a constitutive class II MHC-positive phenotype, the inhibitory effect of TGF-β on class II MHC was abrogated, but the cells remained responsive for expression of TGF-β-inducible genes. Cell lines that possessed defects in TGF-β signaling also became refractory to inhibition of IFN-γ-induced CIITA and class II MHC expression. Our data indicate that TGF-β suppresses IFN-γ-induced class II MHC expression by inhibiting accumulation of CIITA mRNA.