Reduced CaSR expression has been implicated in parathyroid tumorigenesis but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices.Forty sporadic parathyroid adenomas and 10 normal parathyroid tissues were studied. Real time quantitative polymerase chain reaction (qRT-PCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed.qRT-PCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P<0.0001) in parathyroid adenomas. Immunohistochemistry revealed reduced protein expression of CaSR in 85% (34/40) of adenomas. The promoter 2 region of CaSR displayed significant hypermethylation in 45% (18/40) of the adenomas compared to the controls (6.7%;1of 10)(P<0.0001). Bisulphite sequencing analysis revealed maximum methylated CpG at GCM2 binding sites on the CaSR promoter compared to other CpG sites. The methylation status of CaSR correlated directly with plasma iPTH levels in patients with parathyroid adenoma. With ChIP-qPCR analysis, H3K9me3 levels showed increased enrichment by 10-fold in adenomas and correlated with CaSR-mRNA expression (r=0.61; P<0.003). Treatment with 5-aza-2´deoxycytidine restored the expression of CaSR in a parathyroid cell line.Our data suggest that hypermethylation and increased H3K9me3 of the CaSR promoter 2 are involved in silencing CaSR expression in sporadic parathyroid adenoma.