Abstract: Background and purpose: DNA methylation is an important epigenetic modification. Evaluating the status of DNA methylation could be useful for diagnosis, prognostic evaluation and predicting the risk of cancer. Thyroid cancer is the most prevalent endocrine malignancy in humans. This study aimed to screen the aberrant methylated gene in papillary thyroid cancer. Methods: Human primary thyroid cancer tissues and adjacent non-tumor tissues were collected from patients initially surgically treated in the Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center. A total of 95 patients were enrolled in the study. In previous studies, we performed MethylCap-seq and made up a database of genome-wide profiling of methylation in papillary thyroid cancer. Using bioinformatics tools and methylation specific PCR, we screened out the aberrant methylated genes. Results: Using bioinformatics tools, we screened 46 suspicious sites for further research. HOXD10 and FOXD2 were found to have aberrant hypermethylation in their promoter regions. The gene HOXD10 was hypermethylated in 44.4% of cancer tissues and 20.5% of adjacent tissues (P<0.001). The gene FOXD2 was hypermethylated in 54.5% of cancer tissues and 38.6% of adjacent tissues (P<0.001). The hypermethylation of HOXD10 gene was associated with tumor multifocality (OR=3.71), and the hypermethylation of FOXD2 gene was associated with tumor invasion (OR=5.91). Conclusion: The promoters of HOXD10 and FOXD2 may be hypermethylated in papillary thyroid cancer. And the epigenetic modification of HOXD10 and FOXD2 may play a role in tumorigenesis of thyroid cancer.