Fluorouracil Side Effects: What to Expect and When to Call Your Doctor

Fluorouracil (5-FU) is a powerful chemotherapy agent used to treat multiple types of cancer and certain skin conditions. Like all chemotherapy drugs, it comes with a range of potential side effects — from manageable nuisances to serious medical emergencies. Understanding what to expect helps you recognize problems early and know when to seek immediate care.

Side effects differ significantly between IV fluorouracil (used for cancer) and topical fluorouracil cream (used for skin conditions). Both are covered here.

Common Side Effects of IV Fluorouracil (Chemotherapy)

When fluorouracil is given intravenously as part of a chemotherapy regimen, the following side effects are common:

Stomatitis (mouth sores): Painful sores inside the mouth and throat are among the most common side effects of 5-FU. They typically appear 5-10 days after a dose. Using a soft toothbrush, avoiding acidic foods, and rinsing with salt water can help.

Nausea and vomiting: Moderately emetogenic. Anti-nausea medications are typically prescribed alongside your regimen.

Diarrhea: Common and can become severe. Stay well hydrated. Contact your care team if you have more than 4-6 loose stools per day.

Myelosuppression (low blood counts): Fluorouracil reduces white blood cells (neutropenia), red blood cells (anemia), and platelets (thrombocytopenia). Blood counts are monitored regularly.

Hand-foot syndrome (palmar-plantar erythrodysesthesia): Redness, soreness, swelling, or peeling on the palms of hands and soles of feet. More common with continuous infusion than bolus dosing.

Hair thinning: Hair may thin during treatment but typically does not cause complete hair loss as seen with some other chemotherapy agents.

Fatigue: Very common during treatment. Rest, light exercise, and maintaining adequate nutrition can help manage treatment-related fatigue.

Serious Side Effects of IV Fluorouracil — Call Your Doctor Immediately

Some fluorouracil side effects require immediate medical attention. Do not wait for your next scheduled appointment if you experience any of the following:

Chest pain, shortness of breath, or irregular heartbeat: Fluorouracil can cause cardiotoxicity including angina, myocardial infarction, arrhythmia, and heart failure — even in patients with no previous heart disease. Call 911 immediately.

Fever above 100.4°F (38°C): May signal neutropenic fever, which is a medical emergency in chemotherapy patients. Seek immediate care.

Balance problems, confusion, or visual disturbances: Acute cerebellar syndrome is a rare but serious neurological complication of IV 5-FU. Symptoms include loss of balance (ataxia), involuntary eye movements (nystagmus), and confusion. Report these immediately.

Severe diarrhea or GI bleeding: More than 6 watery stools per day, blood in stool, or black/tarry stools require urgent evaluation.

Signs of severe DPD deficiency reaction: Patients with partial or complete DPD deficiency (due to DPYD gene variants) can experience life-threatening toxicity even with the first dose. Symptoms include severe mucositis, profound bone marrow suppression, and neurological symptoms.

Side Effects of Topical Fluorouracil Cream

When fluorouracil cream is used on the skin for actinic keratosis or superficial basal cell carcinoma, the side effects are primarily local skin reactions:

Redness, irritation, and burning at the application site.

Skin crusting, peeling, and swelling — these are expected signs that the medication is working.

Increased sun sensitivity — always use sunscreen and protective clothing while using topical fluorouracil.

Eye irritation if cream accidentally contacts eyes.

Important: Systemic absorption of topical fluorouracil is typically less than 2-6% through normal skin, but can be up to 75 times higher if applied to damaged or diseased skin. Never apply topical fluorouracil to broken, open, or raw skin.

The DPD Deficiency Warning: Critically Important

The most serious safety issue with fluorouracil is DPD deficiency. The DPD enzyme (dihydropyrimidine dehydrogenase) normally breaks down over 80% of 5-FU into inactive metabolites. In patients with DPYD gene variants causing partial or complete DPD deficiency, 5-FU accumulates to dangerous levels. In February 2026, the FDA updated its safety labeling to more strongly recommend DPYD genetic testing before starting fluorouracil or capecitabine.

If you haven't been tested for DPYD variants before starting fluorouracil, talk to your oncologist. For more background on what fluorouracil treats and how it works, see our guide: What Is Fluorouracil? Uses, Dosage, and What You Need to Know.