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There is limited knowledge regarding the blockade of cysteinyl leukotriene receptors (CysLTRs) and their effects in teleost fish. The present study investigated the effects of Zafirlukast, antagonist of CysLTR 1 receptor, on the foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus). Zafirlukast-treated tilapia demonstrated a decrease in the formation of multinucleated foreign body giant cells and Langhans cells on the round glass coverslips implanted in the subcutaneous tissue, along with a significant reduction in white blood cell counts and decreased production of reactive oxygen species. There was an increase in serum levels of α2-macroglobulins, as well as a decrease in ceruloplasmin and haptoglobin. Zafirlukast treatment led to a significant decrease in the area of splenic melanomacrophage centers and a reduction in the presence of lipofuscin. These findings highlight the potential anti-inflammatory effects of zafirlukast treatment in tilapia and indicate its action on CysLTR 1 receptor, modulating the innate immune response of tilapia during the foreign body reaction. The comprehension of chronic inflammation mechanisms in fish has become increasingly relevant, especially concerning the utilization of biomaterials for vaccine and drug delivery., (Copyright © 2023 Elsevier Ltd. All rights reserved.)