Abstract Ticks are notorious blood-sucking ectoparasites affecting both humans and animals, and serve as a unique vector of various deadly diseases. Here, we have shown the roles of the receptor for advanced glycation end-products (RAGE) during repeated infestations by the tick, Haemaphysalis longicornis using RAGE^-/- mice. In primary infestation, a large blood pool developed which was flooded with numerous RBC, especially during the rapid feeding phase of the tick both in wild type (wt) and RAGE^-/- mice. Very few inflammatory cells were detected around the zones of hemorrhage in the primary infestations. However, number of inflammatory cells gradually increased in the subsequent tick infestations and at the 3 ^rd infestations number of inflammatory cells reached to the highest level (350.3±16.8 cells/focus), and the site of attachment was totally occupied by the inflammatory cells in wild type (wt) mice whereas very few cells were detected at the ticks’ biting sites in RAGE^-/- mice. RAGE was highly expressed in the 3 ^rd infestation in wt mice. In the 3 ^rd infestation, infiltration of innate lymphoid cells type 2 (ILC2s), expression of S100A8 and S100B significantly increased at the biting sites of ticks in wt, but not in RAGE ^-/- mice. Also, peripheral eosinophil counts significantly increased in wt but not in RAGE ^-/- mice. Taken together, our study revealed that RAGE-mediated inflammation and eosinophils played crucial roles in the tick induced inflammatory reactions.