We previously showed that CIITA, the HLA Class-II transactivator, inhibits the transcriptional function of Tax-2 and, consequently, the replication of HTLV-II virus in human target cells. Here, we report on an unprecedented interaction between CIITA and Tax-2, that involves the N-term part of CIITA molecule. This interaction could affect the activity of CIITA on endogenous HLA-II promoters. Indeed, while Tax-2 alone does not affect HLA expression, it increases CIITA-mediated expression of HLA-II DR. Interestingly, in the presence of Tax-2, the expression of exogenous CIITA is significantly increased. Tax-2 affects also CIITA ability to interact with components of the HLA-II enhanceosome, such as NF-YB. We ruled out a possible transcriptional effect of Tax-2 on CMV promoter driving the expression of CIITA, because Tax-2 does not increase the expression of other proteins transcribed from the same CMV promoter. The increasing effect mediated by Tax-2 is the result of two contributions: Tax-2 increases the level of CIITA mRNA and enhances CIITA protein stability. Together with our previous observation that CIITA inhibits Tax-2 function, these findings might indicate that HTLV-II virus uses CIITA to negatively control its transcription and to remain latent in infected cells.