DISC21 is a benchmark for large-scale image similarity detection. This benchmark is used for the Image Similarity Challenge at NeurIPS'21 (ISC2021). The goal is to determine whether a query image is a modified copy of any image in a reference corpus of size 1~million. The benchmark features a variety of image transformations such as automated transformations, hand-crafted image edits and machine-learning based manipulations. This mimics real-life cases appearing in social media, for example for integrity-related problems dealing with misinformation and objectionable content. The strength of the image manipulations, and therefore the difficulty of the benchmark, is calibrated according to the performance of a set of baseline approaches. Both the query and reference set contain a majority of ``distractor'' images that do not match, which corresponds to a real-life needle-in-haystack setting, and the evaluation metric reflects that.