Recurrent aphthous stomatitis (RAS) is a common ulcerative condition of the oral mucosa. We assessed minocycline and tetracycline oral rinses in patients with frequent episodes of RAS in a clinical randomized crossover trial. Seventeen patients with high frequency recurrent minor RAS were randomly allocated to a cross-over topical therapy with 0.2 percent minocycline or 0.25 percent tetracycline aqueous solution mouthwash. The minimum interval between the cross-over was 30 days. The intensity of pain was recorded daily using a visual analogue scale. Minocycline mouthwashes as compared to topical tetracycline rinses resulted in significantly improved pain control, by reducing the severity and duration of pain. Topical minocycline rinse may be a potential treatment for other mucosal diseases that result in mucosal ulceration and pain.