Two patients with chronic major aphthous stomatitis of at least 3 years duration were treated with single daily oral doses (1,200 IU) of interferon alfa-2 alpha (HuIFN alpha). Both patients responded with complete remission of aphthae within 6 weeks. One patient had no recurrence of the disease during a 6-month observation period. The second patient had a recurrent aphtha approximately 4 weeks after the initial lesion resolved; however, the recurrent lesion was less severe than the patient had historically experienced. Retreatment of the recurrent lesion with HuIFN alpha resulted in complete remission within 1 week, and there were no further recurrences during the 6-month observational period.