Among the most aggressive tumors is adrenocortical carcinoma. It is still a great challenge to distinguish between adrenocortical adenoma and carcinoma. For many tumors, IGF2 is essential to their growth and development. One of the genes that suppresses tumor growth is SMAD4 and one that may encourage tumorigenesis is PTTG1. Aim of this work: Evaluation of the clinicopathological factors, IGF2, SMAD4, and PTTG1 immuno-expression to distinguish adrenocortical tumors and, consequently, the therapeutic modalities. Material and Methods: A retrospective study was conducted on selected 40 cases of adrenocortical tumors on which immunohistochemical expression of PTTG1, SMAD4, and IGF2- were performed . Receiver operating characteristic (ROC) curves were performed to assess the diagnostic performance of the studied markers as well as clinicopathological variables in discriminating ACA from ACC. Results: Significant differences in tumor size, weight and high Weiss score- were important in differentiating ACA from ACC (p