The c-myb proto-oncogene, which is known to function as a regulator of transcription, is preferentially expressed in hematopoietic cells and is of importance in T-cell differentiation. We recently reported that multiple c-myb binding sites are contained in the 5' flanking region of the human apoptosis gene,/as. Here, we report that, in a gel retardation assay, bacterially-expressed human c-myb protein bound to oligonucleotides corresponding to those fas promoter regions that contained the putative binding motifs for c-myb. In cotransfection assays using COS-7 cells, which do not express c-myb mRNA, an expression plasmid containing wild-type human c-myb transactivated chloramphenicol acetyltransferase reporter plasmids that utilized different segments of the c-myb binding sites contained in the fas promoter region. Expression plasmids containing a mutated form of c-myb were unable to transactivate these reporter plasmids. Transactivation of fas gene expression by c-myb oncogene expression was inhibited after co-transfection with oligonucleotides that were capable of competitively binding c-myb in a human T cell line, Molt-4, and a human B-cell line, LBW-2, but not in a human monocyte cell line, U937. Taken together, these results suggest that c-myb is a transcription activator of human fas and that its functional role in T cells may, in part, be due to the regulation of expression of the fas gene.