The class II transactivator (CIITA) interacts with the chromatin remodeling factor brahma related gene 1 (BRG1) as a necessary component of the transcriptional activation of human major histocompatibility complex (MHC) class II genes. We report here that RFXAP, a subunit of the DNA-binding RFX complex, also binds BRG1 and therefore provides a mechanism by which MHC class II gene chromatin can be remodeled in the absence of CIITA. RFXAP and CIITA bind to different regions of BRG1. The region of the RFXAP protein that binds BRG1 coincides with the minimally required fragment of RFXAP previously reported to be necessary to mediate MHC class II gene transcription. For CIITA, we found that BRG1 interacts with both the N-terminal acidic amino acid rich transactivation domain and a central region of CIITA that contains GTP-binding motifs. Analysis of chromatin structure of MHC class II genes in cell lines lacking CIITA or RFXAP, suggests that the RFXAP-BRG1 interaction may, in some cell types, produce chromatin remodeling.