RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of OVA on days 1 and 14, were challenged with OVA on days 28, 29 and 30 (3, short-term challenge) or on days 28, 29, 30, 36, 40, 44 and 48 (7, repeated challenge) and evaluated 48 hrs later. Anti-mouse RANTES was given intravenously and recombinant mouse RANTES or PBS was administrated intratracheally. These reagents were given on days 28, 29 and 30 in the short-term challenge study and days 44 and 48 in the repeated challenge study. Following short-term challenge, there were no effects following administration of either anti-RANTES or RANTES. In the repeated challenge study, while control mice showed a decrease in airway hyperresponsiveness (AHR), administration of anti-RANTES sustained and enhanced AHR and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN- levels in BAL decreased in the anti-RANTES group, and increased in the RANTES group. IFN- producing CD4 T cells in lung and IFN- production from lung T cells in response to OVA in the anti-RANTES group were significantly decreased, but were increased in the RANTES group. Anti-IFN-, administered with RANTES, decreased effects of RANTES on AHR following repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function following repeated allergen challenge, in part through modulation of levels of IFN- and IL-12.