AS101 as a new immunomodulator has been shown to induce production of a variety of cytokines such as interleukin-1, interleukin-2, colony-stimulating factor, interferon-gamma and tumor necrosis factor, and demonstrate a potential chemo-protection from chemotherapy induced immunosuppression and hematopoietic toxicity in tumor bearing mice and cancer patients on phase I and II clinical trials. This study was designed to verify whether AS101 exerts a cytoprotective effect in rats and mice with gastric lesions induced by intragastric (i.g.) instilling of 0.6N hydrochloride (HCl). AS101 given intraperitoniously (i.p) 2h before a HCl administration markedly prevented HCl-induced gastric lesions both in rats and mice. It also accelerated the ulcer repair when given i.p. 1h after a HCl treatment. Indomethacin (IND), a cyclo-oxygenase inhibitor, given i.p. at a non-ulcerogenic dose of 5mg/kg 1h before AS101 administration, abolished its protective effect. Mechanistic analysis showed that the gastric cytoprotective property of AS101 appears to be mediated through the induction of prostaglandin E2 (PGE2) and epidermal growth factor (EGF), of which, both prevent the gastric mucosa from HCl ulceration while EGF also contributes to the promotion of ulcer repair. This study adds another cytoprotective property to the known immunomodulating role of AS101.