The mud crab (Scylla paramamosain) is widely cultured on the southeast coast of China. Unfortunately, the crab industry has suffered significant economic losses in the past 10 years due to viral, bacterial, and parasitic diseases. Researchers have suggested that using immunostimulants would help establish a crab disease control strategy. However, little information on immune-enhancing proteins in crabs is available. In this study, a quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis was carried out to investigate whether 11 reported genes, including metallothionein (Met), serine protease inhibitor (Spi), lysozyme (Lys), crustin (Cru), catalase (Cat), peroxide reductase (Per), prophenoloxidase (Pro), anti-lipopolysaccharide factor (Alf), Scylla serrata anti-microbial Scy2 pre- cursor, serine proteinase (Sek), and peroxinectin (Per) are associated with enhancing immunity in S. paramamosain treated with rhubarb polysaccharides for 4 days. The results indicate that the mean hemocyte mRNA expression values of Spi, Cat, Per, and Pro increased about 1.1-, 4.1-, 1.2-, and 2.1-fold, respectively. At the same time, the Spi, Cat, Per, Lys, and Alf genes in the hepatopancreas were significantly upregulated. Of these, Spi, Per, and Alf were upregulated 2.1-, 4.8-, and 1.7-fold, respectively. The Lys and Cat genes were only expressed in the experimental group. This result was different from our previous findings that five related immune-enhancing proteins, including hemocyanin, chy- motrypsin, cryptocyanin, C-type lectin receptor, and ferritin protein, were identified in S. paramamosain using proteo- mic and RT-PCR strategies. The discrepancy probably reflects differences between the two research approaches or an uni- dentified post-transcriptional mechanism in these related immune-enhancing proteins. Considering recent evidence that the Spi, Cat, Per, Pro, Lys, and Alf genes play significant roles in invertebrate immune defense, it seems likely that these six significantly upregulated genes in hemocytes and hepatopancreas may be related to enhancing the crab’s im- mune response. These results will help reveal the immune enhancement mechanism in S. paramamosain and will be important for immunological prevention of crab diseases.