5-Fluorouracil (5-FU) is one of most frequently used chemotherapeutic medications for the treatment of many types of cancer in curative and palliative setting. It is important to recognize chemotherapy side effects and toxicities because some of these symptoms may indicate a clinical syndrome needing evaluation for a principal cause. We discuss a patient who developed severe mucositis requiring hospitalization after first use of Fluorouracil. Dihydropyrimidine dehydrogenase ( DPD) deficiency was suspected and was proven to be a cause of severe drug-related toxicity. Our patient is fifty six year old gentleman with stage III nasopharyngeal squamous cell carcinoma who developed two masses on right side of the neck and large posterior right nasopharyngeal mass. Patient was treated with concurrent chemotherapy with high dose of cisplatin along with radiation. Once completion of concurrent chemotherapy and radiation he was started on combination of 5-Fluorouracil and cisplatin. Three days after completion of ninety six hour continuous 5-flurouracil infusion patient developed severe mucositis. Clinical exam was consistent with swollen tongue and mouth and inability to clear oral secretions. Patient was tested for DPYD gene mutation. Testing showed heterozygous for the c.1679T>G(*13) variant in the DPYD gene consistent with predicted intermediate DPD activity (30-70% enzyme activity). About 80% of administered 5-fluorouracil is normally inactivated by DPD. A decrease in DPD enzymatic activity may lead to increased concentrations of 5-FU and elevated risk for severe toxicities. Standard dose of 5-FU was decreased by 50% with second cycle of chemotherapy. Patient tolerated the second cycle of chemotherapy well. Variants in the DPD gene can lead to reduced 5-FU catabolism resulting in severe toxicities. Some of the toxicities can cause death. It is important to screen for this deficiency and closely observe patients during chemotherapy treatment.