To determine the efficacy of Helicobacter pylori gamma-glutamyl-transpeptidase (GGT) in osteoarthritis (OA) therapy. Oral administration of rats with rGGT alleviated joint pain in the acute phase of iodoacetate (IA)-induced OA. The CXCL1/IL-6 in blood and in articular tissue as well as circulating granulocytes in the recipients of GGT, were reduced. This might be associated with the expansion of regulatory T cells in the inguinal lymph nodes and increased articular IL-10. We provide preclinical evidence that H. pylori GGT may represent a promising candidate for OA therapy.