The zinc finger X-linked duplicated A (ZXDA) and ZXDC proteins are both required for robust transcription of major histocompatibility complex class II (MHC II) genes. Aside from the full length ZXDC mRNA transcript, at least one additional mRNA is produced by the ZXDC gene, in which transcription initiates within the first exon and terminates within the seventh intron. The protein product produced from this transcript, which we have named ZXDC2, is truncated on both the N- and C-terminus. We demonstrate here that ZXDC2 functions to repress MHC II transcription induced in HeLa cells treated with IFN-gamma. We further demonstrate that ZXDC2 interacts with both ZXDA and ZXDC, suggesting a mechanism by which ZXDC2 may inhibit MHC II transcription. These studies not only provide additional support for the role of ZXD proteins in regulating MHC II transcription, but also demonstrate a unique mechanism for the synthesis of a mRNA isoform.