<h3>Objectives</h3> There are numerous strategies for the prevention or treatment of oral mucositis. However, their effectiveness is limited and does not correspond to expectations. Recent studies have shown that obestatin exhibits protective effects and accelerates the healing of gastrointestinal mucosa. The aim of the present study was to examine the influence of obestatin administration on oral ulcers in rats. <h3>Study Design</h3> Studies were performed on salivary-intact and sialoadenectomized rats. Gingival ulcers were induced by the use of acetic acid. Rats were treated intraperitoneally twice a day with saline or obestatin (4, 8, or 16 nmol/kg/dose) for 6 days. The study determined the oral mucosa morphology, cell proliferation, mucosal blood flow, and mucosal pro-inflammatory IL-1β level. <h3>Results</h3> In animals with intact salivary glands without induction of oral ulcers, treatment with obestatin was without any effect. Obestatin administration in rats with gingival ulcersbut with intact salivary glands significantly increased healing rate of these ulcers. Obestatin given at a dose of 8 or 16 nmol/kg/dose caused the strongest and similar therapeutic effects. This result was associated with a significant increase in blood flow and cell proliferation in gingival mucosa, as well as a significant decrease in IL-1β level. Sialoadenectomy caused a reduction in cell proliferation and an increase in IL-1β level. Administration of obestatin reversed this effect. In sialoadenectomized rats, the healing rate of ulcers was reduced. As in rats without induction of ulcers, this effect was associated with a reduction in blood flow and cell proliferation in oral mucosa, as well as an increase in mucosal IL-1β concentration. In these rats, obestatin reversed the effect of sialoadenectomy and doses of 8 or 16 nmol/kg increased the healing rate of oral ulcers above a value observed in control rats with intact salivary glands. <h3>Conclusions</h3> Obestatin accelerates the healing of gingival ulcers in both sialoadenectomized and non-sialoadenectomized rats. This therapeutic effect is well correlated with an increase in blood flow and cell proliferation in oral mucosa, as well as decrease of pro-inflammatory IL-1β level. Obestatin is potentially useful candidate for the prevention and treatment of oral mucositis.