Background and Objectives: Colon cancer (CC) has a high mortality rate and is often diagnosed at an advanced stage in Saudi Arabia. Thus, the identification and characterization of potential new cancer-specific biomarkers are imperative for improving the diagnosis of CC by detecting it at an early stage. Cancer-testis (CT) genes have been identified as potential biomarkers for the early diagnosis of various cancers. Among the CT genes are those belonging to theSSXfamily. In order to assess the usefulness ofSSXfamily genes as cancer biomarkers for the detection of early-stage CC, the goal of this research was to validate the expressions of these genes in patients with CC and in matched patients with normal colons (NCs).Materials and Methods:RT-PCR assays were used to analyze theSSX1,SSX2, andSSX3family gene expression levels in 30 neighboring NC and CC tissue samples from male Saudi patients. Epigenetic alterations were also tested in vitro using qRT-PCR analysis to determine whether reduced DNA methyltransferase or histone deacetylation could stimulateSSXgene expression via 5-aza-2′-deoxycytidine and trichostatin treatments, respectively.Results:The RT-PCR results showedSSX1andSSX2gene expression in 10% and 20% of the CC tissue specimens, respectively, but not in any of the NC tissue specimens. However, noSSX3expression was detected in any of the examined CC or NC tissue samples. In addition, the qRT-PCR results showed significantly higherSSX1andSSX2expression levels in the CC tissue samples than in the NC tissue samples. The 5-aza-2′-deoxycytidine and trichostatin treatments significantly induced the mRNA expression levels of theSSX1,SSX2, andSSX3genes in the CC cells in vitro.Conclusions:These findings suggest thatSSX1andSSX2are potentially suitable candidate biomarkers for CC. Their expressions can be regulated via hypomethylating and histone deacetylase treatments, subsequently providing a potential therapeutic target for CC.