White Spot Syndrome Virus (WSSV) is a virulent and widespread dsDNA virus with a wide range of hosts. Although remarkable progress has been made on virus characterization, however, its mechanism of infection is poorly understood. In this study, by analyzing the phage display library of the WSSV genome, a WSSV envelope protein VP187 (wsv209) was found to interact with shrimp integrin. VP187 possesses the RGD motif. The interaction between integrin and VP187 was confirmed with coimmunoprecipitation. These results demonstrate for the first time an interaction between the WSSV envelope protein and a cell surface molecule. Soluble integrin, integrin-specific antibody and an RGD-containing peptide were found to block the WSSV infection in vivo and in vitro. Gene silencing using a sequence-specific dsRNA targeting beta-integrin effectively inhibited the virus infection. These findings suggest that beta-integrin may function as a cellular receptor for WSSV infection.