Oral mucositis is a frequent side effect of cancer therapy. No effective method of prophylaxis is currently available. We conducted a randomized, double-blind, placebo-controlled, crossover trial of pentoxifylline to evaluate its potential in preventing mucositis in cancer patients receiving chemotherapy. Ten cancer patients were randomized for treatment with a 15-day course of 400 mg of pentoxifylline given orally four times daily. Concurrent chemotherapy consisted of bolus cisplatin and infusional 5-fluorouracil. Mucositis was evaluated with the use of the Oral Assessment Guide developed at the University of Nebraska. Patients completing two cycles of chemotherapy--one with pentoxifylline and one with placebo--were evaluated for prophylaxis efficacy. Comparison of the oral assessment scores of the two cycles with a two-sided Student's t test failed to demonstrate a cytoprotective effect for pentoxifylline over placebo. We conclude that pentoxifylline as given in this study is ineffective for preventing mucositis in patients receiving cisplatin and 5-FU.