Background and objectives: Uterine smooth muscle tumors are the most common human neoplasms. They are divided clinically as benign and malignant but there is another group of lesions which is difficult to place in these two categories, so-called (STUMP) and differentiation of these tumors on the basis of H&E staining is impossible. The aim of this study was to find a set of distinguishing objective biomarkers and a survey of immunohistochemical (IHC) markers comparing these three groups of tumors. Materials and Methods: Twenty one (21) cases in each group of the above mentioned tumors were randomly selected (63 cases in total ) from pathobiology laboratories of Kermanshah and Shiraz cities and studied by IHC for expression of ER, PR, C-kit, Bcl-2, P16, and P53 . Results: The frequency of IHC markers expression in leiomyosarcoma (LMS) were as follow: ER (5.26%), PR (15.52%), P53 (26.31%), Bcl-2 (15.78%), C-kit (15.52%) and P16 (15.42%). In the STUMP cases: PR (23.80%), Bcl-2 (4.76%) and P16 (9.52%), ER, C-kit and P53 were not expressed. In Leiomyoma group, only Bcl-2 was expressed (14.28%) and the others had no expression. P53 and P16 expression between the two groups of Leiomyoma and LMS, and also STUMP and LMS were significantly different (P<0.05). Conclusion: P53 and P16 are reliable markers for differentiation between STUMP and LMS and also Leiomyoma from LMS and have a high diagnostic specificity. STUMP is used to identify cases in which clinicopathologic findings for final diagnosis as benign or malignant is not adequate. In this study a high similarity of STUMP group of immunohistochemical profile with benign cases was seen.