Objective: To investigate the expressions of D2-40, CK19, galectin-3, VEGF and EGFR in papillary thyroid carcinoma and their clinical significances. Methods: The expressions of D2-40, CK19, galectin-3, VEGF and EGFR in 38 cases of papillary thyroid carcinoma and 12 cases of thyroid papillary hyperplasia were detected by immunohistochemical staining. Results: The positive expression rates of D2-40, CK19, Galectin-3, VEGF and EGFR in patients with papillary thyroid carcinoma were all significantly higher than those in patients with thyroid papillary hyperplasia (all P<0.05). The expressions of D2-40, VEGF and EGFR in papillary thyroid carcinoma with lymph node metastasis were significantly higher than those without lymph node metastasis (P<0.05). The expressions of CK19 and galectin-3 showed no significant differences between the papillary thyroid carcinomas with and without lymph node metastasis (P>0.05). Conclusions: The detection of D2-40, CK19, galectin-3, VEGF and EGFR is helpful to diagnosis and differential diagnosis of papillary thyroid carcinoma and thyroid papillary hyperplasia. The expressions of D2-40, VEGF and EGFR are associated with lymph node metastasis of papillary thyroid carcinoma, which may be useful for predicting whether or not there is cancer metastasis.