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HER2/neu is overexpressed in about 20% of invasive breast carcinomas. Numerous studies have shown that there is high level of concordance between the HER2/neu status of the primary breast cancer and the metastases of a given patient. Recently, changes in HER2/neu status with tumor progression have been reported, suggesting the possibility of an emerging different tumor clone. Little is known about intratumoral heterogeneity with regard to HER2/neu oncoprotein overexpression. We identified nine cases of invasive ductal carcinoma that showed intratumoral variation in HER2/neu oncoprotein expression by immunohistochemistry. This was confirmed by the intratumoral variation in the amplification status of the HER2/neu gene by fluorescence in situ hybridization and by chromogenic in situ hybridization. The results of this study suggest that some cases of primary breast carcinoma are heterogeneous in regard to HER2/neu gene amplification or protein overexpression. Heterogeneity of HER2/neu status in a tumor may be a rare event or underestimated. This phenomenon should be examined as it may contribute to a better understanding of the variation in therapeutic responses and the conflicting data in studies about the prognostic and predictive role of HER2/neu status in subsets of breast cancer patients.