Low salinity is one of the main factors limiting the distribution and survival of marine species. As estuarine species, Crassostrea hongkongensis can live in relative low salinity. Through Illumina sequencing, we generated two transcriptomes with samples taken from gills of oysters exposed to the low salinity seawater versus the optimal seawater. By RNAseq technology, we found 13550 up-regulation genes and 9914 down-regulation genes that may regulate osmotic stress in C. hongkongensis. As blasted by GO annotation and KEGG pathway mapping, functional annotation of the genes recovered diverse biological functions and processes. The genes regulated significantly were dominated in structural molecule activity, intracellular,cytoplasm protein metabolism, biosynthesis,cell and transcription regulator activity according to GO annotation. The study aimed to compare the expression data of the two transcriptomes to provide some useful insights into signal transduction pathways in oysters and offer a number of candidate genes as potential markers of tolerance to hypoosmotic stress for oysters. In addition, the characterization of C. hongkongensis transcriptome will facilitate research into biological processes underlying physiological adaptations to hypoosmotic shock for marine invertebrates. Overall design: Twelve oysters were exposed in low salinity (8‰) seawater and in optimal salinity (25‰) seawater,respectively. Gills from six oysters in each condition were balanced mixed respectively. The transcriptomes of two samples were generated by deep sequencing, using Illumina HiSeq2000