Perfluoroalkyl compounds (PFCs) as food contaminants are widely distributed persistent organic pollutants (POPs) and have been suggested to induce immune dysfunction. However, their effects on immune function are not conclusive. Mast cells play a central role in allergic and non-allergic inflammatory responses. Therefore, we have examined the effects of PFCs (PFHxS, PFOA, PFOS) on mast cell-mediated inflammatory responses using in vitro mouse bone marrow-derived mast cells (BMMCs) and human mast cells (HMC-1) and in vivo mice model. The effects of PFCs were compared with those of bisphenol A (BPA), a well-studied environmental pollutant. Among PFCs tested, PFOS had the highest effects. Both PFOS and BPA increased degranulation and production of inflammatory eicosanoids in mast cells at a similar level, which subsequently led to increased skin edema and serum LTC₄ and PGD₂ in mice. Both PFOS and BPA increased not only downstream signaling (PLCγ1, AKT, ERK), but also upstream signaling (Fyn, Lyn, Syk/LAT) in mast cells. Taken together, PFOS and BPA induce mast cell-mediated inflammatory responses via a common signaling pathways. Our results may help establish the scientific basis for understanding the etiology of mast cell-mediated inflammatory responses and improve the immune dysfunction risk assessment for emerging POPs such as PFCs.