Objective To analyze the expression differences of FoxP3 protein in papillary thyroid carcinoma (PTC) and nodular goiter, and to explore the correlation between FoxP3 and the clinicopathological characteristics of PTC patients and the therapeutic dose of 131I. Methods Immunohistochemical method was used to detect the expression of FoxP3 protein in 128 cases of PTC tissues (42 cases were treated with 131I after operation) and 20 cases of nodular thyroid tissues, and the relationship between it and the clinicopathological characteristics of PTC patients and the dose of 131I treatment was also analyzed. Results The positive rate of FoxP3 protein expression in PTC tissues was 46.09%, which was higher than that in nodular goiter tissues (0.00%), and the difference was statistically significant (P<0.001). The expression of FoxP3 protein in PTC was correlated with gender, extraglandular invasion and tumor diameter (P values were 0.041, 0.039, and 0.007, respectively), but had no correlation with age, capsular invasion, TNM staging, lymph node metastasis, and distant metastasis (P>0.05). The results of binary logistic regression analysis suggest that tumor diameter was an independent risk factor affecting FoxP3 protein expression [OR=0.389, 95%CI (0.180, 0.840), P=0.016]. By drawing the receiver operating characteristic (ROC) curve, it was shown that the area under the curve (AUC) was 0.643 when the tumor diameter was 1.05 cm, the sensitivity to predict the increase in FoxP3 protein expression was 64.41%, and the specificity was 57.97%, P=0.006. Among 42 patients with PTC who underwent 131I treatment after surgery, the therapeutic dose of 131I was related to the expression of FOXP3 protein (P=0.031). It was shown that patients with positive expression of FoxP3 protein were given more dose of 131I after surgery. Conclusions The positive rate of FoxP3 protein expression in PTC is higher than that of nodular goiter. Its high expression means that the patient has poor pathological characteristics and larger 131I treatment dose, suggesting that FoxP3 may be involved in the malignant progression of PTC.