Transport of mRNA from the nucleus to the cytoplasm is still a poorly understood process in which RNA signal sequences and cognate RNA-binding proteins may be involved. We have analysed the transport of the mRNA encoded by HLA-DRA, a member of the immunologically important MHC class II multigene family. We report that, in transient transfection experiments, HLA-DRA mRNA molecules encompassing a signal situated in the 3' untranslated region predominantly accumulate in the nucleus. We also show that the RNA sequence involved interacts with compartmentalized proteins of either nuclear or cytoplasmic origin. Deletion of the mRNA region encompassing this retention site results both in the abrogation of protein binding and in the release of HLA-DRA mRNA into the cytoplasm. In addition, we have found that the distribution of these HLA-DRA mRNA binding proteins is different in different cell types; in particular, their pattern of expression in Ntera-2, a human teratocarcinoma cell line, is distinct from that observed in Raji, a human B-lymphoma cell line, and is modulated by growth in retinoic acid. We conclude that recognition of a mRNA retention signal by proteins located in different compartments on either side of the nuclear membrane may regulate the nucleo-cytoplasmic partitioning of HLA-DRA transcripts and, perhaps, of MHC class II mRNA in general.