The zinc finger protein ZNF202 is a transcriptional repressor that binds to promoter elements predominantly found in genes involved in lipid metabolism. Here we demonstrate that ZNF202 mRNA expression is inversely correlated with ATP binding cassette A1 (ABCA1), ABCG1, and apolipoprotein E (apoE) in human monocytes. Upregulation of ABCA1, ABCG1, and apoE expression during monocyte differentiation and foam cell formation was accompanied by a simultaneous downregulation of both ZNF202 mRNA isoforms m1 and m3. Conversely, deloading of macrophage foam cells with HDL3 caused upregulation of ZNF202 mRNA. To further characterize the transcriptional regulation of the ZNF202 gene, comparative genomic sequence analysis and reporter gene assays were performed. The ZNF202 core promoter region resides within 247 bp upstream of the transcription initiation site and is highly active in THP-1 monocytes, yet downregulated upon macrophage differentiation. Using site-directed mutagenesis, we show that two highly conserved transcription factor binding sites, a GC-box and an Ets-binding motif, are required for ZNF202 gene expression. Furthermore, electrophoretic mobility shift assays demonstrate in vitro binding of PU.1 and GC-box binding proteins to the ZNF202 proximal promoter. We conclude that the inversely correlated transcriptional activity of ZNF202 and its target genes during macrophage differentiation may reflect a direct regulatory interdependence and thus provide further evidence for ZNF202 as an important gatekeeper of lipid efflux.