The myeloid-specific leukocyte integrin CD11d encodes the alphaD subunit for the alphaDbeta2 receptor. A yeast one-hybrid screen showed that a longer isoform of gut-enriched Kruppel-like factor 4 (GKLF) we term GKLFa interacts with the CD11d promoter. Purified GST-GKLFa protein was shown to bind within the -61 to -44 region that overlaps a binding site for the CD11d transcriptional activators Sp1 and transforming growth factor beta-inducible early gene-1 (TIEG1). Transfection of GKLF/GKLFa in myeloid cells reduced CD11d promoter activity, whereas, down-regulation of GKLF/GKLFa with small interfering RNAs led to up-regulation of CD11d expression. Differentiation of myeloid cells with phorbol ester led to activation of the CD11d promoter and reduced occupancy of the promoter by GKLF/GKLFa but an increased occupancy by TIEG1 in vivo. Binding of GKLF/GKLFa, Sp1, and TIEG1 to the CD11d promoter in vivo is dependent on their zinc finger DNA binding domains. GKLFa physically associates with the histone deacetylases (HDAC) 1 and 2, and both HDACs are bound to the CD11d promoter in vivo but released after exposure of myeloid cells to phorbol ester suggesting that GKLF/GKLFa recruits HDACs to effect repression.