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Abstract Background Histopathology images are critical for medical diagnosis, e.g., cancer and its treatment. A standard histopathology slice can be easily scanned at a high resolution of, say, 200,000×200,000 pixels. These high resolution images can make most existing imaging processing tools infeasible or less effective when operated on a single machine with limited memory, disk space and computing power. Results In this paper, we propose an algorithm tackling this new emerging “big data” problem utilizing parallel computing on High-Performance-Computing (HPC) clusters. Experimental results on a large-scale data set (1318 images at a scale of 10 billion pixels each) demonstrate the efficiency and effectiveness of the proposed algorithm for low-latency real-time applications. Conclusions The framework proposed an effective and efficient system for extremely large histopathology image analysis. It is based on the multiple instance learning formulation for weakly-supervised learning for image classification, segmentation and clustering. When a max-margin concept is adopted for different clusters, we obtain further improvement in clustering performance.