Objective: To investigate the clinical value of the combined detection of high-mobility group box-1 (HMGB-1) and tumor-specific growth factor (TSGF) for diagnosis of thyroid cancer. Methods: The serum levels of HMGB-1 and TSGF in 86 patients with pathologically confirmed thyroid cancer, 78 cases with nodular goiter and 69 healthy individuals as control were detected by using ELISA kits, and the correlations of the serum levels of HMGB-1 and TSGF with the clinicopathologic parameters were analyzed. Results: The differences in the levels of both HMGB-1 and TSGF among the three groups had statistical significances (both P<0.05), of which, both levels were the highest in thyroid cancer patients, followed by those in nodular goiter patients, and the lowest in the healthy subjects. The area under curve (AUC) of the combination of HMGB-1/TSGF was 0.912, which was significantly higher than that of HMGB-1 or TSGF alone (both P<0.05). In patients with thyroid cancer, the serum levels of HMGB-1 and TSGF were unrelated to sex, age, lymph node metastasis or clinical stage (all P>0.05). Conclusion: The combination detection of HMGB-1 and TSGF may have certain application value for the early diagnosis of thyroid cancer.