Introduction: Breast lesions are very common diseases worldwide. Benign breast disease (BBD) accounting for most breast problem in females. Carcinoma breast is one of the most common human neoplasms rapidly replacing cancer of cervix as the most important leading site of cancer in most urban populations of India. A panel of antibodies, improved antigen retrieval techniques have all contributed to the use of immunohistochemistry (IHC) in solving diagnostic problems in breast pathology. Materials and methods: This is a cross-sectional study done in a hospital in Tumkur, Karnataka for 1.5 years. Total of 41 benign and 41 malignant biopsies of breast neoplasm from female patients was studied. All breast masses were analyzed systematically by clinical history, physical examination, histopathological examination along with the immunohistochemical study of CK 5/6. All collected data were entered into a master sheet and fed into computer software for statistical analysis using Pearson's Chi-square test. Results: In our study patients belonged to the age group of 15 –70 years. Benign lesions were common in the age group of 21–30 years, and malignant lesions were common in the age group of 51–60 years. The most frequent benign neoplasm was a fibroadenoma (74%) and in malignancy, infiltrating ductal carcinoma-NOS (85%). Most of the malignant cases were of size T2 (76%) and grade II (66%) and without any lymph node metastatic deposits (83%). All benign breast lesions showed positive expression for CK 5/6; the staining index of benign lesions varied from 5–9. Fibroadenomas showed stain index range of 6–8. Highest stain index of 9 was seen in fibrocystic with ductal epithelial hyperplasia. In malignant lesions, all cases were negative for CK 5/6 expression except 3 IDC-NOS cases which were grade III (poorly-differentiated) and showed weak CK 5/6 expression with stain index of 2.There was a statistically significant association between CK 5/6 stain index with grading and lymph node metastasis. Conclusion: Immunohistochemistry (IHC) is an integral part of the pathology. Although hematoxylin and eosin (H&E) stain remain the gold standard method for diagnosis, IHC provides useful vital information in grey zone cases. CK 5/6, as a component of panels along with AE1/AE3 and myoepithelial markers, help to differentiate benign and malignant breast lesions in cases of interobserver variability. Grade III breast carcinoma cases, if positive for CK 5/6, imply a ‘basal-like’ molecular phenotype and signify a poor prognosis. These tumors require aggressive intervention. CK 5/6 can help provide prognostic information and better treatment modalities.