Down syndrome is mainly caused by a trisomy of chromosome 21. The Down syndrome critical region 2 (DSCR2) gene is located within a part of chromosome 21, the Down syndrome critical region (DSCR). To investigate the function of DSCR2, we sought to identify DSCR2-interacting proteins using yeast two-hybrid assays. A human fetal brain cDNA library was screened, and DSCR2 was found to interact with a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptor beta, (PPARbeta). A co-immunoprecipitation assay demonstrated that DSCR2 physically interacts with PPARbeta in mammalian HEK293 cells. DSCR2 also inhibited the ligand-induced transcriptional activity of PPARbeta. Furthermore, PPARbeta also decreased the solubility of DSCR2, which increased levels of insoluble DSCR2.