Background: The incidence of differentiated thyroid cancer in Mainland China has increased rapidly in recent years, yet the number of studies focusing on health-related quality of life (HR-QOL) is still limited. Additionally, some of the quality-of-life (QOL) issues specific to thyroid cancer have not been adequately described. The aims of this study were to assess the generic and disease-specific HR-QOL of differentiated thyroid cancer survivors and to identify the associated factors. Methods: A cross-sectional survey including 373 patients was conducted in Mainland China. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Thyroid Cancer-Specific Quality of Life Questionnaire (THYCA-QOL), and a questionnaire on patient demographics and clinical characteristics. Results: The QLQ-C30 global mean score was 73.12 (standard deviation [SD] = 11.95), while the THYCA-QOL summary mean score was 34.50 (SD = 12.68). The two QLQ-C30 functional subscales with the lowest scores were the social functioning and role functioning subscales. The five symptom subscales of the THYCA-QOL with the highest scores were the subscales regarding less interest in sex, problems with scar, psychological problems, voice problems, and sympathetic problems. Factors associated with worse global QOL on the QLQ-C30 included a shorter time since completing primary treatment (≤6 months), a history of lateral neck dissection, and a lower current thyrotropin (TSH) level (≤0.5 mIU/L). Higher cumulative activities of radioiodine (RAI; >100 mCi), gender (women), postoperative hypoparathyroidism, and a history of lateral neck dissection were associated with worse thyroid cancer-specific QOL. In contrast, higher monthly household income (>5000￥) and a history of minimally invasive thyroid surgery were associated with better thyroid cancer-specific QOL. Conclusions: Thyroid cancer patients experience multiple health-related problems and disease-specific symptoms after completing primary treatment. Patients with a duration ≤6 months from the completion of primary treatment, those with a history of lateral neck dissection, and a current TSH level ≤0.5 mIU/L may be more likely to have impaired generic QOL. More thyroid cancer-specific symptoms may be associated with higher cumulative activities of RAI, gender (women), postoperative hypoparathyroidism, a history of lateral neck dissection, lower monthly household income, and conventional surgery.

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