Recurrent aphthous stomatitis (RAS) is a common ulcerative condition of the oral mucosa. In this study, minocycline oral rinses were compared to a placebo in patients suffering from frequent episodes of RAS. Thirty-three patients with RAS were randomly allocated to topical therapy with 0.2% minocycline or a placebo aqueous solution mouthwash. Seven patients also participated in a blind crossover study. The intensity of pain was recorded daily using a visual analogue scale. Minocycline mouthwashes resulted in significant reduction in the severity and duration of pain due to RAS. The findings in the subgroup that participated in the crossover were consistent with outcomes in the randomized study. The findings of this study show that minocycline oral rinses reduce pain in patients with RAS and may have implications for the use of minocycline in other non-infectious inflammatory ulcerative oral mucosal diseases.