SH2D1A, the X-linked lymphoproliferative disease (XLP) gene, encodes a cytoplasmic protein that plays an essential role in controlling Epstein-Barr virus infection. It is expressed in T and NK cells, but not in B cells or in granulocytes. The promoter, the regulatory regions, as well as the mechanisms controlling its tissue-specific expression, are still unknown. We tested the hypothesis that DNA methylation might contribute to tissue-specific SH2D1A gene expression and analyzed the methylation status of 2,300bp upstream of the ATG starting codon, the coding region and part of intron1. By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, we show that a differential methylation pattern of CpG-rich regions in the 5 region and the adjacent exon1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription.