A portion of a cDNA clone corresponding to the 3' end of the human quinonoid dihydropteridine reductase (QDPR) mRNA was used as a probe to physically map the QDPR gene by analysis of somatic cell hybrid lines. The provisional assignment of QDPR to chromosome 4, based on expression of the human enzyme in hybrids, was confirmed. The gene was further regionally localized on the short arm to 4p16.1----4p15.1. This physical localization places QDPR in the same area of the genome that contains the defect causing Huntington's disease (HD). The QDPR probe revealed a restriction fragment length polymorphism with the enzyme BanII, permitting determination of its genetic proximity to D4S10, an anonymous DNA marker tightly linked to HD. QDPR is only loosely linked to D4S10, excluding any primary role for the gene in HD.