The nuclear signaling evoked by phosphoinositide‐ specific‐phospholipase C (PI‐PLC)beta1 targets specific regions of Cyclin D3 as well CD24 promoter, hinting at a role in haematopoiesis, given that both Cyclin D3 and CD24 are involved in the very early steps of this process. PI‐PLCbeta1 could also play a role in the progression of Myelodysplastic Syndromes (MDS) into Acute Myeloid Leukemia (AML) since the mono‐allelic deletion of PI‐PLC beta1 is responsible in MDS patients for a higher risk of evolution to AML. Given that a single patient treated with azacitidine, a DNA methyltransferase inhibitor, displayed a direct correlation between PI‐PLCbeta1 gene expression and drug responsiveness, we hypothesized that PI‐PLCbeta1 could be a target for demethylating therapy. By quantifying the degree of PI‐PLCbeta1 methylation and gene expression in MDS patients at baseline and during azacitidine administration we found an increase of PI‐PLCbeta1 mRNA in responder patients and a reduction of promoter methylation. The molecular response correlated to and anticipated the clinical one, suggesting that PI‐PLCbeta1 gene reactivation predicts azacitidine responsiveness. Our results demonstrate for the first time that PI‐PLCbeta1 promoter is hypermethylated in high‐risk MDS patients and that the amount of PI‐PLCbeta1 mRNA predicts the clinical response to azacitidine.