We have studied whether mouth-swishing with sucralfate, a well-known gastric mucosal protective agent, may be used as prophylaxis against chemotherapy-induced stomatitis. Using radioactively labelled sucralfate we found that 20-30% was still bound to the oral mucosal lining 2 1/2 h after mouth-swishing. Forty patients receiving cisplatin and continuous infusion with 5-fluorouracil (5-FU) for 5 days entered a double-blind placebo-controlled cross-over study. Among 23 evaluable patients a significant reduction (p = 0.04) in an objective score of edema, erythema, erosion and ulcerations was seen during treatment with sucralfate. Patient preference favored sucralfate, but this preference failed to reach statistical significance (p = 0.06). Seven patients were inevaluable for reasons not associated with the study treatment. However, ten patients did not complete the study since the swishing procedure aggravated chemotherapy-induced nausea. An equal rate of non-compliance was seen with sucralfate and placebo. To overcome this problem, the oral medication should have a neutral taste, the solution should not be swallowed after the swishing, which should not be started until the nausea had ceased.