Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. This study was a genome-wide methylation analysis of PTC. The study was conducted at the National Institutes of Health Clinical Center. PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. CpG methylation status was assessed using advanced genome-wide methylation bead chips. Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS).