Objective: To evaluate the efficacy of cyanocobalamin treatment in patients having recurrent aphthous ulcers (RAUs) with normal or decreased serum vitamin B12 (cobalamin) levels. Methods: Seventy-two patients with RAU were included in the study. In addition to serum cobalamin levels, hemanitic and biochemistrical parameters were measured. Patients with serum cobalamin levels <140 pg/mL were defined as the cobalamin deficient group (CDG) whereas patients with cobalamin levels 140 pg/mL were defined as the cobalamin normal group (CNG). The degree of aphthous ulcer healing was determined according to serum cobalamin levels at the first and sixth month after cyanocobalamin treatment protocol. Results: Of the 72 participants, 37 were in the CDG whereas 35 were considered to have normal cobalamin levels. In the first admission the cobalamin levels were 215.8 +/- 116.90 pg/mL in CNG and 107.43 +/- 29.35 pg/mL in the CDG. The frequency of aphthous ulcers was defined numerically according to monthly occurrence of the lesions. The mean aphthous ulcer frequency in CNG group was 1.9 +/- 0.7, whereas it was 2.4 +/- 0.9 in the CDG. A significant increase in cobalamin levels was observed after cyanocobalamin treatment in both groups. A significant decrease in aphthous ulcer frequency was also concurrently observed. 96% of the patients showed good response to replacement treatment, 4% of the study population did not respond to the treatment. Conclusion: Cyanocobalamin treatment maybe beneficial for patients with RAU even when serum cobalamin levels are normal. We suggest that higher serum cobalamin levels should be attained in patients with RAU for mucosal protection.