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Widespread outbreaks of mandarinfish (Siniperca chuatsi) ranavirus (MRV) have emerged in many mandarinfish farms in Guangdong, the most important region of the mandarinfish industry in China. Unlike the early typical clinical signs of abnormally swollen abdomens due to extremely severe ascites, diseased fish from the reemerging natural outbreaks of MRVs had little ascites but showed lethargy, anorexia and a typical sleepy syndrome. The disease duration of the natural outbreak of MRV could last for 1 to 5 months. Additionally, the majority of the surviving fish showed persistent anorexia and body emaciation and deformity, which is also very different from the symptoms of mandarinfish infectious spleen and kidney necrosis virus (ISKNV)—the notorious and well-known iridoviral agent in the mandarinfish industry. Mandarinfish vaccinated with the ISKNV-inactivated vaccine showed no protective effect against the natural outbreak of MRV, whereas the ISKNV vaccine seamed to induce a stronger outbreak of the MRV disease in MRV carrier fish. By real-time quantitative PCR, the liver, spleen, kidney as well as intestine are shown to be the major viral reservoirs, both under artificial infection and natural outbreak. Additionally, histopathology, immuno-histochemistry, immunofluorescence assay and transmission electron microscopy also confirmed the pathogenicity of MRV to mandarinfish. Collectively, the emerging MRV disease remained a severe and actual threat to the mandarinfish industry. As two different genera members in the family Iridoviridae , the ISKNV vaccine provided no cross-protection against MRV. A combination vaccine, containing both ISKNV and MRV, is urgently needed. • Outbreaks of MRV in both natural and ISKNV-FKC vaccinated mandarinfish; • Natural MRV diseases showed persistent infection, characterization by lethargy, anorexia and a typical sleepy syndrome; • ISKNV-FKC vaccine showed no cross protection against MRV infection, whereas could induce a stronger outbreak of MRV; • Histopathology, IHC and IFA were characterized in MRV-infected mandarinfish. [ABSTRACT FROM AUTHOR]