BACKGROUND: Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family. KGF protects the oral and intestinal mucosa against damage induced by irradiation or chemotherapy. Previous studies have found the expression of KGF in chondrocytes and suggested that KGF promotes the wound healing process in injured cartilage. KGF also has important effects on the immune system such as the regeneration of thymus tissue and the formation of regulatory T cells (T(reg)) in the periphery. AIM: Here we investigated the effect of KGF on collagen type II induced arthritis (CIA) and anti-collagen antibody induced arthritis (CAIA) in order to discriminate between immunoregulatory effect and direct protective effect on chondrocytes. METHODS: CIA was induced by immunization with CII and CAIA by treatment of mice with a cocktail of four different anti-CII antibodies. The effect of KGF on the thymus and spleen was analyzed by FACS and by immunohistochemistry. RESULTS: We have found that KGF treatment delayed the onset of CIA but had no effect on CAIA. Our results show that KGF treatment leads both to an outflow of naive T cells from the thymus and to a statistically significant increase in the percentage of CD4(+)Foxp3(+) T(regs) in the periphery. CONCLUSIONS: We suggest that the effect of KGF on CIA depends on immunoregulatory mechanisms. KGF may delay the aging of the cellular immune system and thus improve the resilience of the immune system against autoimmune reactions. © Informa UK, Ltd.