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Triphenyl phosphate (TPHP) is one of the most widely used organic phosphorus flame retardants and is ubiquitous in the environment. Studies have been reported that TPHP may lead to obesity, neurotoxicity and reproductive toxicity, but its impact on the immune system is almost blank. The present study was aimed to investigate the potential immunotoxicity of TPHP on macrophages and its underlying mechanism. The results demonstrated for the first time that TPHP (12.5, 25, and 50 μM)‐induced F4/80+CD11c+ phenotype of RAW 264.7 macrophages, accompanied by increased mRNA levels of inflammatory mediators, antigen‐presenting genes (Cd80, Cd86, and H2‐Aa), and significantly enhanced the phagocytosis of macrophage. Meanwhile, TPHP increased the expression of Toll‐like receptor 4 (TLR4), and its co‐receptor CD14, leading to significant activation of the downstream ERK/NF‐κB pathway. However, co‐exposure of cells to TAK‐242, a TLR4 inhibitor, suppressed TPHP‐induced F4/80+CD11c+ phenotype, and down‐regulated inflammatory mediators and antigen‐presentation related genes, via blocked the TLR4/ERK/NF‐κB pathway. Taken together, our results suggested that TPHP could induce macrophage dysfunction through activating TLR4‐mediated ERK/NF‐κB signaling pathway, and it may be the potential reason for health‐threatening consequences. [ABSTRACT FROM AUTHOR]