Ghrelin, an acylated 28-amino acid polypeptide, was primary isolated from the stomach, and the stomach is a main source of circulating ghrelin. Ghrelin strongly and dose-dependently stimulates release of growth hormone from the anterior pituitary, as well as increases food intake and fat deposition. Previous studies showed that ghrelin exhibits protective and therapeutic effect in different parts of the gastrointestinal system, including the oral cavity. The aim of present study was to examine the role of growth hormone and insulin-like growth factor-1 (IGF-1) in the healing of gingival ulcers. Studies were performed on rats with the intact pituitary gland and hypophysectomized rats. In anesthetized rats, chronic ulcers of the gum were induced by acetic acid. Rats were treated intraperitoneally twice a day with saline or ghrelin (4, 8 or 16 nmol/kg/dose) for six days. In pituitary-intact rats, administration of ghrelin significantly increased serum concentration of growth hormone and IGF-1 and this effect was associated with a significant increase in the healing rate of gingival ulcers. Moreover, treatment with ghrelin increased mucosal blood flow and DNA synthesis in the gum, while a local inflammation was decreased what was observed as a reduction in mucosal concentration of pro-inflammatory interleukin-1β. Hypophysectomy decreased serum level of growth hormone below a detection limit; whereas serum concentration of IGF-1 was reduced by 90%. On the other hand, removal of the pituitary gland was without any significant effect on the healing rate of gingival ulcers or on the ulcer-induced increase in DNA synthesis and concentration of pro-inflammatory interleukin-1β in gingival mucosa. Administration of ghrelin failed to affect serum level of growth hormone and IGF-1 in hypophysectomized rats, and was without any effect on the healing rate of gingival ulcers, mucosal blood flow, DNA synthesis or concentration of interleukin-1β in gingival mucosa. Neither induction of gingival ulcers nor hypophysectomy nor administration of ghrelin significantly affected serum concentration of pro-inflammatory interleukin-1β. We concluded that endogenous growth hormone and IGF-1 were involved in the therapeutic effect of exogenous ghrelin in the healing of gingival mucosa damage.