Major histocompatibility complex (MHC) class II genes are expressed constitutively in only a few cell types, but they can be induced in the majority of them, in particular by interferon-γ (IFN-γ). The MHC class II transactivator gene CIITA is defective in a form of primary MHC class II deficiency. Here it is shown that CIITA expression is controlled and induced by IFN-γ. A functional CIITA gene is necessary for class II induction, and transfection of CIITA is sufficient to activate expression of MHC class II genes in class II-negative cells in the absence of IFN-γ. CIITA is therefore a general regulator of both inducible and constitutive MHC class II expression.