Sea bass (Lateolabrax maculatus) is an important mariculture fish and is widely cultured along the coast of China. As the culture of L. maculatus continue to increase in terms of scale and density, so will the potential occurrence of viral diseases. Infectious spleen and kidney necrosis virus (ISKNV), a species of the genus Megalocytivirus, causes a serious systemic disease with high morbidity and mortality in both freshwater and marine fishes. Therefore, it is crucial to verify the immune mechanism of L. maculatus against ISKNV. Interferon-stimulated gene 15 (ISG15), a member of the ubiquitin gene family, plays important roles in the innate immune response, regulation of interferon signaling, and pregnancy in human. In this study, the cDNA sequence of LmISG15 was cloned and analyzed. The full length of LmISG15 cDNA is 1625 bp, with an open reading frame (ORF) of 480 bp encoding 160-amino acid protein, a predicted molecular weight of 17.5 kD and a theoretical isoelectric point of 9.41. The amino acid sequence of LmISG15 contains two UBL domains located at 1?76 and 85?155 respectively, and the C-terminal domain contains LRGG motif as the C-terminal of ubiquitin. The deduced amino acids sequence of LmISG15 shared 74.07% and 71.88% identity with ISG15 of Sciaenops ocellatus and Oplegnathus fasciatus, respectively. LmISG15 was constitutively expressed in various tissues, with the highest expression level in heart, and then brain, kidney and gill, and the lowest level was detected in muscle of ISKNV-infected L. maculatus. After challenged with ISKNV, the transcript levels of LmISG15 peaked in the head-spleen at 48 h, and in the liver and gill at 72 h. The expression of LmISG15 in the three tissues gradually returned to normal at 5d after reaching the peak. The increased expression of LmISG15 in various tissues of L. maculatus following ISKNV infection implies the potential involvement of LmISG15 in the immune response of sea bass.