Common fragile sites represent components of normal chromosome structure that are particularly prone to breakage under replication stress. Although the cytogenetic locations of 88 common fragile sites are listed in the Genome database, the DNA at only 14 of them has been defined and characterized at the molecular level. Here, we identify the precise genomic position of the common fragile site FRA1E, mapped to the chromosomal band 1p21.2, and characterize the genetic complexity of the fragile DNA sequence. We show that FRA1E extends over 370kb within the dihydropyrimidine dehydrogenase (DPYD) gene, which genomically spans approximately 840kb. The 185kb region of the highest fragility, which accounts for 86% of all observed breaks at FRA1E, encompasses the central part of DPYD including exons 13-16. DPYD encodes dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme in a three-step metabolic pathway involved in degradation of the pyrimidine bases uracil and thymine. Deficiency in human DPD is associated with autosomal recessive disease, thymine-uraciluria, and with severe 5-fluorouracil toxicity in cancer patients. To which extent the disruption of the DPYD gene by the fragile site break is only transient, followed by DNA repair to restore the original structure, or occasionally may result in genomic damage associated with human disease remains to be determined.