Background/aim: A number of tumor markers detected in the serum or pathological specimens using immunohistochemical methods are used for early detection of malignancies and postoperative follow-up. Human leukocyte antigen-G (HLA-G) is a nonclassic HLA class I molecule. Recent studies suggested a relationship between HLA-G positivity and the stage or the phenotype of the malignancy. In this study, the relationship between serum HLA-G positivity and thyroid cancer was investigated. Materials and methods: Fifty patients with thyroid cancer and 45 healthy volunteers were included in this study. Serum HLA-G levels were measured using ELISA. Results: HLA-G was positive in only 3 out of 50 patients with thyroid cancer (2 papillary, 1 follicular type). On the other hand, HLA-G was positive in 20 out of 45 healthy subjects (P < 0.001). The prevalence of detectable levels of serum HLA-G was independent of sex and age in the whole study population. No correlation was found between serum HLA-G value and thyroid hormone profile, neither in papillary thyroid cancer nor follicular thyroid cancer patients. Conclusion: In this study, serum HLA-G was significantly less common in patients with thyroid cancer than in healthy controls.