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Clinical laboratory testing for HER2 status in newly diagnosed, primary breast cancer tissues is critically important for therapeutic decision making. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating proteins through the direct and morphology-driven analysis of tissue sections. Unlike immunohistochemistry (IHC), MALDI-IMS enables the acquisition of complex protein expression profiles without any labeling. We hypothesized that MALDI-IMS may determine HER2 status directly from breast cancer tissues. Breast cancer tissues (n=48) predefined for HER2 status by IHC and fluorescence-in-situ-hybridization (FISH) were subjected to MALDI-IMS and protein profiles were obtained through direct analysis of tissue sections. Protein identification was performed by tissue micro-extraction and fractionation followed by top-down tandem mass spectrometry on a spherical ion trap with ETD. A discovery and an independent validation set were used to predict HER2 status by applying proteomic classification algorithms. We found that specific protein/peptide expression changes strongly correlated with the HER2 over expression (m/z 4740, 8404, 8419, 8455, 8570, 8607, 8626). Among these, we identified m/z 8404 as Cysteine-rich intestinal protein 1 (CRIP1). Of particular note, the proteomic signature was able to accurately define HER2-positive from HER2-negative tissues achieving high values for sensitivity of 83%, for specificity of 92% and an overall accuracy of 89% (95% CI: 65% to 99%). Our results underscore the potential of MALDI-IMS proteomic algorithms for morphology-driven tissue diagnostics such as HER2 testing and show that MALDI-IMS can reveal biologically significant molecular details from tissues which are not limited to traditional high-abundance proteins. CRIP1 is a cytosolic protein that is potentially useful for serum based diagnostics of HER2 if tissue leakage can be demonstrated.