Oral mucositis is a major toxic effect related to 5-fluorouracil (5-FU) therapy. Clinical studies have attempted to identify an effective antidote for this untoward side effect. Early pilot studies suggested that an allopurinol mouthwash could lessen 5-FU-induced mucositis. However, a randomized, double-blinded, placebo-controlled crossover study did not suggest that an allopurinol mouthwash had any prophylactic value in this clinical situation. An ongoing, randomized clinical protocol is testing cryotherapy as a method of inhibiting 5-FU-induced stomatitis. No clinically appropriate prophylactic measure for preventing 5-FU-induced mucositis has been found to date.