Renal cell carcinoma (RCC) is the most aggressive form of genitourinary malignancy. Tryptophan 2, 3-dioxygenase (TDO2) is the primary enzyme that catalyzes tryptophan to kynurenine. TDO2 is overexpressed in a variety of malignancies. Forkhead box protein 3 (FOXP3) serves as a master regulator in maturation of regulatory T cells (Treg), but recently its expression found in cancer cells. Aim: To elucidate value of FOXP3 and TDO2 expression in RCC. Materials and Methods: In this retrospective study, 66 renal cell carcinomas and 10 cases of non-neoplastic renal tissue- were examined. TDO2 and FOXP3 immunohistochemical staining was conducted, evaluated for each case and correlated with clinic-pathological findings. Results: Significant statistical correlations were observed between TDO2 expression and grade, size, renal sinus invasion, nodal metastasis, and stage (P= 0.03, 0.0001, 0.005, 0.018 and 0.0001 respectively). Tumor FOXP3 expression and grade, renal sinus invasion, renal venous thrombosis, lymph node metastasis, and stage- were significantly associated (P= 0.0001, 0.0001, 0.003, 0.001, and 0.0001, respectively). The relationship between FOXP3+ Treg and grade, size, capsular invasion, renal sinus invasion, and stage- was significant (P= 0.0001, 0.034, 0.023, 0.033, and 0.002, respectively). The statistical correlations between the expression of TDO2 and tumor FOXP3 and FOXP3+Treg, as well as among the expression of tumor FOXP3 and FOXP3+Treg- were highly significant (P value < 0.01). Conclusion: TDO2 and FOXP3 may have role in tumorigenesis and progression of RCC and could be potential markers for targeted therapy.