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The ability to detect failures and anomalies are fundamental requirements for building reliable systems for computer vision applications, especially safety-critical applications of semantic segmentation, such as autonomous driving and medical image analysis. In this paper, we systematically study failure and anomaly detection for semantic segmentation and propose a unified framework, consisting of two modules, to address these two related problems. The first module is an image synthesis module, which generates a synthesized image from a segmentation layout map, and the second is a comparison module, which computes the difference between the synthesized image and the input image. We validate our framework on three challenging datasets and improve the state-of-the-arts by large margins, i.e., 6% AUPR-Error on Cityscapes, 7% Pearson correlation on pancreatic tumor segmentation in MSD and 20% AUPR on StreetHazards anomaly segmentation."