Background: Papillary breast neoplasms are heterogenous group of breast diseases consisting of wide range of benign, atypical and malignant lesions. Evaluation of such papillary neoplasms is considered one of the most problematic issues in diagnosis of breast pathology depending on H&E only as they need different interventional treatment modalities. Aim of study: To differentiate papillary breast lesions depending on immunohistochemical staining of P63, SMA, CK14, chromogranin and ER. Materials and Methods: An Immunohistochemical study of P63, SMA, CK14, chromogranin and ER were conducted on 75 cases of different papillary breast neoplasms; papilloma (20 cases ) , DCIS ( 25 cases ) , solid papillary carcinoma ( 12 cases ), intracystic papillary carcinoma ( 11cases) and invasive micropapillary carcinoma (7 cases) . Results: Out of 75 cases, all cases of duct papillomas were positive to SMA, P63. Ninety percent (90 %) of them were positive to CK14 in comparison to malignant papillary: DCIS, intracystic papillary carcinomas. solid papillary carcinomas neoplasms which were negative (84.0%, 92.3 %, 90.0% & 100.0%, respectively). Ninety -two percentage (92 %) of DCIS cases, 92.3% intracystic papillary carcinomas, 90.0% solid papillary carcinomas and all cases of invasive micropapillary carcinomas-showed homogenous positivity for ER compared to papillomas that showed focal heterogenous expression with statistical significant (p<0.01). Solid papillary carcinoma cases were diffusely positive for chromgranin. P63 was more specific than SMA and CK14 in diagnosis of ductal papilloma (100% Specificity). chromogranin was more specific in discriminating solid papillary carcinoma (95.0% Specificity) .ER was the most sensitive marker in diagnosis of malignant papillary lesions (92.7 % sensitivity). Conclusion: A combined panel of markers consisting of P63, SMA, CK14, chromogranin and ER-could be helpful in differentiating begin, atypical and malignant papillary breast lesions which need different interventional treatment modalities. A wider scale study on different variants of malignant papillary lesions is recommended.