Intraductal proliferative lesions of the breast have traditionallybeen divided into three categories: Usual ductal hyperplasia (UDH),atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS).However the term DCIS encompasses a highly heterogeneous group oflesions that differ with regard to their mode of presentation,histopathologic features, biological markers and risk for progression toinvasive cancer. CK5/6 is of value in differentiating ductal proliferationof varying degrees especially in the differentiation between cancerousand non-cancerous changes. S-100 protein was shown to be present inmyoepithelial and epithelial cells of the mammary gland. The aim of thisstudy is to examine the immunohistochemical profiles for CK5/6 & S-100in 40 Egyptian adult females’ breast lesions with subsequent investigationof their potential diagnostic significance. The cases were subdivided into25 cases of benign epithelial lesions including UDH, 5 cases of ADH, &10 cases of DCIS. CK 5/6 positive expression was detected in 24 out of25 benign epithelial lesions of the breast (96%), and was detected in fourout of five atypical ductal hyperplasia (80%), and was detected in 2 out of10 (20%) ductal carcinoma in situ. S100 positive expression in bothepithelial and myoepithelial cells was detected in all benign epitheliallesions of the breast (100%), and four out of five atypical ductalhyperplasia (80%), and in one out of ten ductal carcinoma in situ (10%).It is noteworthy that S100 showed a higher level of significance thanCK5/6, in distinction between malignant versus both atypical and benignlesions. The former also had a higher sensitivity, specificity and accuracyrates than CK5/6.So simultaneous detection of CK5/6 and S100 proteinexpression can help increase the diagnostic accuracy of breast diseases.