The regulation by IFN of the expression of HLA-B7 and HLA-A3 class I molecules was studied in Jurkat human T lymphoma cells, HHK EBV-transformed human B lymphocytes, and murine HLA-B7 HLA-A3 co-transfected L fibroblasts. Jurkat cells express constitutively low level of HLA class I molecules and treatment with human IFN resulted in preferential increase of the expression of HLA-B7 molecules, the expression of the HLA-A3 molecules being relatively unchanged. Similar treatment of HHK cells, which express constitutively large amount of HLA class I molecules, resulted in a marginal increase of the expression of both HLA-B7 and HLA-A3 molecules. HLA-B7 HLA-A3 co-transfected L cells express relatively low level of HLA class I molecules, expression of both however was significantly increased after treatment with murine INF-alpha, the augmentation being more accentuated for HLA-B7 molecules. In all cases, variations of cell surface expression were related to parallel modifications of the level of HLA-B7 and HLA-A3 RNA transcripts. Important nucleotide differences exist between the IFN consensus sequences associated with the HLA-B7 and HLA-A3 class I genes. Using oligonucleotides corresponding to these sequences two patterns of retarded bands were observed by the gel mobility shift assay, suggesting that the IFN-mediated differential regulation of the expression of the HLA-B7 and HLA-A3 genes could be due to different nuclear regulatory factors.