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Background: Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor. This study aimed to investigate the gene and protein expression of RAP1GAP and DNA methylation patterns of its CpG74a, CpG74b, and CpG24 in an Iranian population with MTC. Methods: In this case-control study, we selected 55 individuals who underwent thyroidectomy in Erfan hospital, Tehran, between 2018 and 2020. Samples were divided into normal thyroid tissues (control; n = 20), benign nodule (n = 20), and MTC (n = 15). DNA methylation patterns were investigated using MSP (methylation-specific PCR). The protein level and mRNA expression of RAP1GAP were also evaluated using western blotting and real-time PCR, respectively. Results: The hyper-methylation rates of CpG24 and CpG74a in the MTC samples were considerably higher than the controls (83% versus 15% and 74% versus 17%, respectively; P < 0.001). The methylation/unmethylation ratio of CpG74a, and CpG24 was considerably higher than the controls (P < 0.001). The methylation/unmethylation ratio of CpG24 in the benign nodules was also considerably greater than the controls (P < 0.001). The mRNA expression and the protein level of RAP1GAP in the MTC group were considerably lower than the controls (P = 0.005 and P = 0.035, respectively). In the MTC group, aberrant methylation of CpG74a and CpG24 was significantly correlated with decreasing expression of the RaplGap gene (R2: 0.23; P = 0.032 and R²: 0.56; P = 0a.001, respectively). Conclusion: Hyper-methylation in CpG24 and CpG74a and decreasing expression of RAP1GAP can be considered as diagnostic biomarkers for MTC. [ABSTRACT FROM AUTHOR]