A disintegrin and metalloprotease with trombospondin motifs (ADAMTS) is a family of proteins characterized by the presence of a metalloproteinase domain linked to a variety of specialized ancillary domains. ADAMTS18 is a putative tumor suppressive gene related to nasopharyngeal carcinoma. We used high-resolution melting (HRM) analysis to detect the methylation levels of ADAMTS18 gene in 100 gastric cancers, 100 colorectal cancers, 70 pancreatic cancers, and equal number of adjacent normal tissues. The frequency of ADAMTS18 methylation in all three types of cancers was significantly higher than that in normal tissues. Expression levels of ADAMTS18 were inversely correlated with methylation levels. No significant association was found between ADAMTS18 methylation status and TNM staging in the cancers. In summary, epigenetic regulation of ADAMTS18 was associated with carcinogenesis. The application of HRM analysis is a fast and high-throughput way to investigate the epigenetic status of ADAMTS18.