In order to find the immune-relevant factors responsible for the virus resistance in the WSSV-resistant shrimp, a suppression subtractive hybridization method was employed to identify differentially expressed genes and their expression profile in the hepatopancreas of the virus-resistant penaeid shrimp. Thirty five genes were identified from more than 400 clones, of which eight are found for the first time in penaeid shrimp. betaGBP is the most abundant gene in our subtractive library except hemocyanin. Lectin, ferritin, oxygenase and chitinase of the virus-resistant shrimp all showed up-regulation in expression compared with those of normal shrimp. In addition, Ranbp, Rho and Rab were found in the subtractive library. This is the first evidence indicating that small GTPases are involved in the signal transduction in shrimp defense response. Furthermore, a number of genes encoding apoptotic-related proteins and antioxidant enzymes were expressed at a higher level in the virus-resistant shrimp. In short, the high expression of immuno-related genes in response to the virus infection and the involvement of small GTPases in the antiviral response provide a new insight for further study in the crustacean innate immunity.