Background: APOE is involved in immunological control mediated by lymphocytes. The biological processes of several malignant tumors were accelerated by its overexpression. APOE reduces antigen-activated lymphocytes, which has an impact on immunity. Regulatory T cells (Treg) are a subset of T helper (CD4+) cells, which are essential to the immune system because they counteract the actions of T cells to decrease autoimmune reactions. For this regulation, the transcription factor forkhead box (FOXP3) is crucial. Due to their involvement in the onset and progression of PTC, APOE and FOXP3 may be utilized in molecularly targeted treatments. Immunocheck-point inhibitors are essential to support novel immunotherapy approaches in treatment and increase the prognosis of PTC linked with HT since both indicators have significant immunoregulatory processes. Our aim of this study is to explore the effect of APOE and FOXP3 on PTC prognosis and its clinical outcome, which could help in novel treatments development against PTC. Methods: 46 tissue blocks were obtained retrospectively spanning the period between May 2018 to May 2023. These sections are then exposed to all steps of IHC technique for staining of APOE and FOXP3. SPSS 23.0 was used to computerize and statistically evaluate the data .Chi-sq test (χ2) and Fisher exact were used to calculate the difference between qualitative variables. Overall and Progression-free survival were estimated by using Kaplan and Meier’s method . A P-value of less than 0.05 shows significance. Results: The analysis showed there was a significant association between the expression of APOE and FOXP3 and various prognostic factors such as tumor size, grade, stage, lymphovascular invasion, recurrence, and mortality. Conclusions: Increased tissue expression of novel immunomarkers APOE and FOXP3 are associated with poor clinical outcome which predicted the possibility of using these markers as targeted therapy in combination with the ordinary used therapies for improving the prognosis of PTC with associated HT. Keywords: APOE; FOXP3; PTC; Prognosis; IHC