Stomatitis is a common adverse effect of intravenously infused 5-fluorouracil (5FU). Although there are encouraging studies about the preventive role of oral cryotherapy in stomatitis induced by intravenous administration of 5FU, this simple and cost-effective method is not part of clinical practice. This prospective randomized study investigates whether oral cryotherapy alleviates 5FU-induced stomatitis. Thirty six patients, included in the cryotherapy group, were instructed to hold ice cubes in their oral cavity, shortly before, during and shortly after the infusion of 5FU. Both mean physician and patient-graded stomatitis of our cryotherapy group were compared with those of a control group (40 patients) and were found significantly reduced for all three chemotherapy cycles. The percentage of patients who were free from oral toxicity was significantly higher in the cryotherapy group in all three chemotherapy cycles, as judged both by patients and physicians. The results of this study encourage the use of cryotherapy in patients receiving 5FU in alleviating stomatitis by using a side-effect-free, easy to perform and inexpensive measure, which does not interfere with the efficacy of antineoplastic agents.