We previously found that the MHC-II transactivator CIITA inhibits HIV-1 replication in human T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 of Positive Transcription Elongation Factor b (PTEF-b). In this study we analyzed the anti-viral function of CIITA in myeloid cells, the other relevant HIV target cell type. We used the U937 promonocytic Plus and Minus clones, characterized by efficient or inefficient capacity to support HIV-1 replication, respectively. This different phenotype has been also associated with the viral restriction action of TRIM22 because this factor is expressed in U937 Minus but not in Plus cells. We demonstrate that CIITA is expressed only in Minus cells and as a consequence of this, Tat-dependent HIV-1 LTR transactivation is inhibited. Indeed, the stable expression of CIITA in Plus cells inhibited Tat-mediated activation of the viral LTR and reduced HIV-1 replication with respect to Plus parental cells. This result was independent from TRIM22 because CIITA did not induce TRIM22 expression in Plus transfected with CIITA. Thus, CIITA acts as a viral restriction factor against HIV-1 not only in T cells but also in monocytes. Nevertheless, Tat transcriptional activity and HIV-1 replication were inhibited to a lesser extent in Plus cells transfected with CIITA with respect to Minus cells, suggesting that CIITA and TRIM22 might still work in concert to counteract HIV-1 infection and spreading. These results will be discussed in the context of the present knowledge of cell permissivity to HIV-1 replication and to the possible involvement of specific these restriction factors in the generation and maintenance of HIV-1 silent reservoirs.