We have looked for the binding of several HOX4 complex homeoproteins in the genomic region containing the HOX4C promoter, between the human HOX4C and HOX4D genes. The HOX4C, HOX4D and Hox-4.3 homeoproteins bind to a phylogenetically highly conserved DNA fragment, which is located in the proximal part of this intergenic region and contains multiple binding sites for these HOX4 proteins. Using cotransfection experiments, we show that this endogenous DNA sequence can mediate transactivation by the HOX4D and HOX4C proteins and that this effect requires the presence of TAAT-related binding sites. The Hox-4.3 protein, in contrast, is unable to activate and can repress the activation observed with the two other proteins. These results show that the HOX4D and HOX4C genes are genuine sequence-specific transcription factors and suggest that, as in Drosophila, cross-regulatory interactions between these genes might be essential for their proper expression.