The MAPK/ERK pathway transmits extracellular signals through a kinase cascade consisting of RAF, MEK and ERK into the nucleus to initiate proliferation, differentiation or apoptosis. The magnitude and duration of pathway signalling is tightly regulated by the induction of negative feedback regulators, which include the dual-specificity phosphatase (DUSP) family of MAPK phosphatases (MKP). The negative regulator of MAPK/ERK signalling, DUSP5, has recently been shown to be epigenetically inactivated in gastric cancer, and postulated to be a putative tumour suppressor gene in these tumours. To determine whether DUSP5 is similarly inactivated in colon cancer, we examined DUSP5 gene methylation status in a panel of colon cancer cell lines. Robust CpG Island Methylation of DUSP5 was observed in 17% of the lines examined. Notably, DUSP5 methylated cell lines were enriched for those that harboured BRAF mutations, and the CpG island methylator phenotype. To confirm these findings in patient samples we determined the methylation status of DUSP5 in 15 matched tumour/ normal pairs from colon cancer patients by bisulphite-sequencing. This analysis revealed higher DUSP5 methylation levels in tumours than in control samples. These findings demonstrate that like gastric cancers, DUSP5 is frequently methylated in colon cancers.