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We present a new, simple, and high\u2010throughput platform for multi\u2010color epigenetic analysis. The novelty of our approach is the ability to multiplex methylation and de\u2010methylation signals in the same assay. We utilize an engineered methyltransferase enzyme that recognizes and labels all unmodified CpG sites with a fluorescent cofactor. In combination with the already established labeling of the de\u2010methylation mark 5\u2010hydroxymethylcytosine via enzymatic glycosylation, we obtained a robust platform for simultaneous epigenetic analysis of these marks. We assessed the global epigenetic levels in multiple samples of colorectal cancer and observed a 3.5\u2010fold reduction in 5hmC levels but no change in DNA methylation levels between sick and healthy individuals. We also measured epigenetic modifications in chronic lymphocytic leukemia and observed a decrease in both modification levels (5\u2010hydroxymethylcytosine: whole blood 30\u2009%; peripheral blood mononuclear cells (PBMCs) 40\u2009%. 5\u2010methylcytosine: whole blood 53\u2009%; PBMCs 48\u2009%). Our findings propose using a simple blood test as a viable method for analysis, simplifying sample handling in diagnostics. 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