Gene-specific hypermethylation has previously been detected in Arsenic exposed persons. To monitor the level of whole genome methylation in persons exposed to different levels of Arsenic via drinking water, DNA was extracted from peripheral blood mononuclear cells of 64 persons. Uptake of methyl group from 3H labeled S-Adenosyl Methionine after incubation of DNA with SssI methylase was measured. Results showed statistically significant (P = 0.0004) decrease in uptake of 3H methyl group in the persons exposed to 250–500 μg/L arsenic, indicating genomic hypermethylation. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.