Objective To explore the effectiveness of preventing oral ulcer by using high dose methotrexate with calcium folinate and sodium bicarbonate gargle alternatively.Methods Sixty patients of high dose methotrexate chemotherapy were randomly divided into experiment group and control group, with 30 patients in each group, Normal saline was given to those in the control group for gargle, and calcium folinate and sodium bicarbonate gargle alternatively for those in the experiment group, The incidence and grade of oral ulcer were observed.Results The incidence of oral ulcer and grade were markedly lower in the experiment group than that in control group. The difference between the two groups was significant(P<0.01).Conclusions Alternate gargling with calcium folinate and sodium bicarbonate is effective in the prevention of incidence of oral ulcer in patients with high dose methotrexate chemotherapy.