Background: It is beneficial to distinguish non- invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from other follicular-based lesions like follicular variant of papillary thyroid carcinoma (FVPTC) and follicular adenoma (FA). Galectin-3 plays a role in normal development and tumorigenesis. Cytokeratin 19 (CK19) overexpression is linked to neoplastic transformation. PD-L1 functions as a negative immune regulator. Hypoxia-inducible factor (HIF-1α) plays a role promoting angiogenesis. Aim: Evaluation role of Galectin-3, CK19, PD-L1 and HIF-1α immunoexpressions in distinguishing between benign follicular nodule (BFN), NIFTP and FVPTC with correlation to different clinicopathological variables hoping to find new diagnostic and therapeutic methods. Material and Methods: This retrospective study was done on 45 cases of different thyroid follicular-patterned lesions as follows: 25 BFN, 6 NIFTPs, and 14 cases of FVPTCs. Immunohistochemical staining was used to detect Galectin-3, CK19, PD-L1 and HIF-1α expressions in distinguishing those follicular-patterned thyroid lesions. Results: PD-L1, Galectin-3 and CK19 showed the highest sensitivity and specificity in distinguishing FVPTCs from BFNs and NIFTPs when used individually. In many configurations, the panel made up of the four markers (positive Galectin-3, positive CK19, positive PD-L1 and high HIF-1α) showed the highest specificity and sensitivity (100% and 88.4% correspondingly). PD- L1 was the most sensitive marker (92.8%), whereas Galectin-3 and CK19 were the most specific (80%) to discriminate FVPTCs from BFNs and NIFTPs. Conclusion: The co-expression of Galectin-3, CK19, PD-L1, and HIF-1α increased specificity and sensitivity (100% and 88.4% respectively) while differentiating FVPTCs from BFNs and NIFTPs.