Mast cells express multiple metabotropic purinergic receptor (P2YR) subtypes; however, only few studies have evaluated the role of these receptors in human mast cell (HMC) allergic response as measured by degranulation through FcεRI-activation. We have previously shown that extracellular nucleotides modify the FcεRI-activation-dependent degranulation in HMCs derived from human lungs, but the mechanism of this action has not been fully delineated. The present study was undertaken to determine the mechanism of P2YR’s activation on HMC degranulation and elucidate the specific post-receptor mechanistic steps/pathways involved. Sensitized LAD2 cells, a human derived mast cell line, were subjected to a weak allergic stimulation (WAS) using a low concentration of antigen in the absence and presence of the P2Y₁₁R agonist, ATPγS. In the presence of ATPγS, WAS-induced degranulation was enhanced by sevenfold. None of the other P2YR agonists tested, including high concentrations of ATPγS, enhanced WAS-induced intracellular Ca²⁺ mobilization, which is an important regulator of degranulation. Both PI3K inhibitor and the relevant gene knock-down decreased the ATPγS-induced enhancement of degranulation. ATPγS effect was associated with enhanced phosphorylation of PI3K(δ) and Akt. The effects of ATPγS were dose dependently inhibited by NF157, a P2Y₁₁R antagonist and were reduced by treatment with P2Y₁₁ mRNA knock-down in LAD2 cells. We determined for the first time that at least one subtype of P2YR, P2Y₁₁R, is linked to enhancement of allergic degranulation in HMCs independent of Ca²⁺ mobilization.