is a commercially important oyster species in East Asia as it is edible during the summer when the other oyster species are unavailable. Salinity is one of the important limiting factors to the survival and distribution of this stenohaline species. The molecular mechanism behind the response of this species to hypo-salinity stress remains unclear. Quantitative Real-Time PCR (qRT-PCR) has been widely used for the analysis of gene expression. The optimal reference gene is constantly transcribed in different types of cells, tissues, and species and under various experimental conditions. However, reference genes that meet all of these conditions are almost non-existent. The selection of a proper reference gene is a precondition for accurate analysis of the expression level of a target gene in quantitative real-time PCR. A total of five candidate reference genes, elongation factor 1a (EF1A), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), heterogeneous nuclear ribonucleoprotein A2/B1 (RO21), -tubulin (TUB), and α-tubulin (TUA), were analyzed by qRT-PCR in four tissues (gill, mantle, visceral mass, and adductor muscle) under three salinity conditions of 10, 20, and 30 psu for one week. Three algorithms, geNorm, NormFinder, and BestKeeper, were used to evaluate the expression stability of the candidate reference genes. The results showed that EF1A was most stable in the different tissues under normal conditions. Under salinity stress, GAPDH was the most stable gene according to overall ranking. In contrast, TUB and TUA were the least stable genes and were not suitable as reference genes. This study showed that different algorithms may generate inconsistent results. Therefore, a combination of several reference genes should be selected to accurately calibrate system errors, especially for studies of different tissues in which candidate reference genes have more unstable expression. The present study was the first to select reference genes by qRT-PCR and to provide a useful basis for selecting appropriate reference genes. The present study also has important implications for gene expression and functional genomics research related to salinity stress in this species or other bivalve species.