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The mouse and human CD3G and D genes are organized in opposite transcriptional orientation, their 5' ends being separated by about 1.6 kilobases (kb) of DNA. The molecular basis of the tissue-specific regulation of expression of the human CD3G and D genes were examined using DNase I hypersensitivity and CpG methylation analysis. Two T cell-specific DNase I hypersensitivity sites were defined within the intergenic region. A third hypersensitive site (DHS3) was detected 0.4 kb 3' to the CD3D gene. This latter site was present in all T cells, but was absent in all other committed cell types examined. DHS3 was also detected in the lympho-myeloid progenitor cell KG1, but was absent when this line was induced to differentiate to the macrophage lineage. The intergenic region was undermethylated in T cells expressing CD3, but was in general more extensively methylated in other cell types. Importantly, however, in KG1 sublines which express the CD3 genes the intergenic region remains extensively methylated. These results define areas 3' to the D gene and within the intergenic region which contain regulatory elements that influence both CD3D and G expression. They further show that transcription from the CD3D and G genes may occur initially from a methylated promoter. Significantly, the 3' regulatory region was shown to adopt an open chromatin structure prior to lineage commitment and before CD3 transcription.