MARCH5, as an E3 ubiquitin ligase, is one of the important immune regulatory factors in mammals. To investigate the immune function of MARCH5A in large yellow croaker, Larimichthys crocea, the full-length cDNA of MARCH5A was identified in this study (named LcMARCH5A). The full-length of MARCH5A cDNA is 1045 bp, containing an ORF of 867 bp which encoded a 288 aa protein with one RINGv domain and four trans-membrane domains. The analysis of phylogenic tree showed that there are 11 MARCH family proteins, same as those in mammals. However, there are many isoforms of MARCH proteins in fishes, and MARCH5A is fish-specific gene copy, and there are some differences in physical and chemical parameters and spatial structure between LcMARCH5A and LcMARCH5B. Tissues distribution showed that MARCH5A transcripts were broadly distributed in all detected tissues, with high expression in blood and heart, moderate in gill and brain, low in kidney and skin as indicated by qRCR analysis. After Cryptocaryon irritans challenge, the mRNA of MARCH5A was significantly up-regulated early in the skin and reached a peak with 9.65-fold to the control at day 2, then down-regulated thereafter. In the gill, spleen and head-kidney, the expression also increased early, and later decreased. These results showed that MARCH5A plays an important role in fish defense against C. irritans infection.