Objective: To investigate the relationship of preoperative serum Cyfra 21-1 with clinicopathology and prognosis of differentiated thyroid cancer (DTC) patients. Methods: Totally 124 patients with DTC, 152 patients with thyroid benign tumors, and 66 health examination professionals from January 2013 to June 2016 in Southwest Hospital Affiliated to Third Military Medical University were reviewed. The levels of serum Cyfra 21-1 between the three groups were compared. Clinicopathological variables associated with the preoperative level of serum Cyfra 21-1 and their prognostic value were analyzed. Results: The level of serum Cyfra 21-1 in the DTC and benign tumor groups were significantly higher than that in the normal control group (all P<0.01). But the differences of serum Cyfra 21-1 between the DTC and benign tumor group were not significant (all P>0.05). The level of preoperative serum Cyfra 21-1 was significantly correlated with pathological type, TNM stage, lymphatic metastasis and local invasion (all P<0.05), and not related to gender, age and tumor size (all P>0.05). The 5-year disease-free survival rate of DTC patients was 83.3%. Univariate analysis showed that postoperative recurrence was associated with gender, pathological type, TNM stage, lymphatic metastasis, local invasion and the level of preoperative serum Cyfra 21-1 (all P<0.05). Multivariate analysis showed that late TNM stage and high level of preoperative serum Cyfra 21-1 were independent risk factors for postoperative recurrence (All P<0.05). Conclusion: The level of preoperative serum Cyfra 21-1 could not help diagnosis DTC, but they can prompt some clinicopathologic features. Serum Cyfra 21-1 was a potential independent prognostic factor for postoperative recurrence of DTC patients.