C4A and C4B are closely related homologous complement proteins encoded in the class III region of major histocompatibility complex (MHC). The regulation of their expression is under genetic and hormonal control. In this study we investigated the synovial fluid plasma ratio of C4A and C4B of rheumatoid (RA) and osteoarthritis (OA) patients, and a predominance of the C4B gene expression by the synovial macrophages of RA patients was demonstrated. To clarify the tissue specificity of the expression of C4A and C4B genes, human monocytoid cell line U937 and hepatoma-derived HepG2 cells were studied. The gene expression of C4A and C4B were markedly different in these cells since a relative predominance of C4B mRNA in U937 cells and excess of that of C4A in HepG2 cells were detected. Recombinant interferon-gamma (IFN-gamma) up-regulated the expression of C4A gene in both cells, but had apparently no effect on the C4B gene. Our results demonstrate dissimilar expression patterns for the two human C4 genes, suggesting different tissue specific regulation of human C4A and C4B.