OTUD6B is a member of the ovarian tumor protease (OTU) family and was initially considered as an inactive DUB.[22] It has been reported to regulate protein synthesis in non‐small cell lung cancer cells[23] and inhibit hepatocellular carcinoma metastasis independent of its catalytic activity.[24] Here we show that OTUD6B reduces Ub(n)‐ubiquitinylated substrates, especially polyubiquitin chains, demonstrating that it is a bona fide DUB. This evidence concerns the gene ZUP1 and hepatocellular carcinoma.