OBJECTIVES: To develop and test an integrated approach to human epidermal growth factor receptor 2 (HER2) copy number analysis in breast cancer using in situ hybridization (ISH) and cytogenomic microarray (CMA). METHODS: CMA was performed on four clinical breast cancer samples with nonclassical patterns of HER2 ISH results. Integrated analysis was performed by correlating the data from pathology review, ISH, and CMA. RESULTS: Integrated analysis provided a more comprehensive view of the genomic copy number landscape that informed HER2 copy number analysis, but ISH provided essential data in all cases. CONCLUSIONS: CMA can be helpful for clarifying HER2 amplification status in breast cancer. However, uncertainties over tumor percentage, clonal heterogeneity, and varying ploidy levels present challenges for genomic methods such as CMA. Accurate interpretation of HER2 copy number by CMA requires correlation with the pathology and ISH data.