Abstract Background: Most genome-wide methylation studies have focused on technology to profile and identify therapeutic biomarkers in HCC. However, attempts to integrate these technologies to clinical and population based studies are still lacking. Objective: Our aim was to identify existing methylation profiling technologies that can be used in translational epigenomic efforts. Methods: We examined Quantitative Methylation specific PCR, oligonucleotide methylation tiling arrays (MeDIP-chip), and Methylation BeadChip arrays and their ability to distinguish between HHC cases and controls, a key goal in Phase I biomarker development trials. Scatterplots, histograms and heat maps of genome-wide DNA methylation array data were used to provide a snapshot of the differences in methylation patterns between tumor and normal samples. Results: The representative tumor sample had a lower methylation score median and less significant genome-wide methylated probes (1,503) than either normal liver tissue samples (2,585 and 2,2887 respectively). RASSF1A and B4GALT1 had a sensitivity of 52%, a specificity of 100% and an AUC of 0.73 (RASSF1A) and 0.75 (B4GALT1). SSBP2 had a sensitivity of 38%, a specificity of 100% and an AUC of 0.58. A panel combining these genes with HCC risk factors had a sensitivity of 87%, a specificity of 100% and an AUC of 0.91. Conclusions: We have shown that genome-wide and gene-specific methylation platforms, which interrogate gene promoter regions, can be used to examine novel biomarkers and differentiate HCC from normal liver tissue. Additional studies will confirm the value of using methylation-profiling technologies to evaluate these new markers as we move forward. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3172. doi:10.1158/1538-7445.AM2011-3172