Fragile X syndrome is the most common form of inherited mental retardation disease, resulting from absent of expression of its disease geneFMR1. To study the function of the fragile X mental retardation protein (FMRP) through protein/protein interaction, a mouse embryo cDNA library was screened by the yeast two-hybrid system. A clone was found to interact specifically with FMRP. The cDNA of this clone (Genbank accession number af 102875) encoded a protein highly homologous to human G/T mismatch-specific DNA thymine glycosylase (hTDG). Interactions between various alternatively spliced FMRP isoforms and a series of mTDG deletion proteins were further studied in the yeast two-hybrid system and their interaction amino acid regions were determined. Interaction between FMRP and TDG existed inside exon 13 of FMRP (amino acid residue 397–425) and around amino acid residue 122–346 of TDG. These results will be helpful to the study of the biological role of FMRP.