Background and Objective: Anti-CK5/6 monoclonal antibodies have an established role in breast disease diagnosis. Anti-CK5 monoclonal antibodies have recently become commercially available. There has been growing interest in the staining characteristics of anti-CK5 and its potential diagnostic role in place of anti-CK5/6. We aim to compare and contrast the staining characteristics of anti-CK5/6 vs anti-CK5. Material and Methods: 58 tissue blocks containing 122 different lesions were selected from tissue archives. Two specimens (groups) were taken from each lesion One (group) was stained with anti-CK5 and the other (group) with anti-CK5/6 monoclonal antibodies, using the Streptavidin-biotin immuno-peroxidase method. The two groups of slides were compared and contrasted for lesion staining pattern and for intensity, using light microscopy. Results: Results showed that the diagnostic staining pattern was exactly the same in both anti-CK5 and anti-CK5/6 groups, and also showed that anti-CK5, stained most of the lesions more intensely than anti-CK5/6. Conclusion: Anti-CK5 performed at least as well (for lesion-pattern staining), and better (for lesion staining intensity) than did anti-CK5/6 in the diagnosis of a wide range of breast tissues and lesions. It may be justified to safely replace anti-CK5/6 with anti-CK5 in future routine clinical use, with resultant diagnostic and economic benefits.