Abstract: A rare phenomenon of SDS-induced activation of a latent protease activity associated with the purified silkworm excretory red fluorescent protein (SE-RFP) was noticed. SE-RFP aliquots incubated with SDS for different time intervals indicated that the protein undergoes an obligatory breakdown into a number of subunits which exhibit autoproteolytic (acting upon themselves) and/or heteroproteolytic (acting on other proteins) activities. A strong serine protease activity of SE-RFP subunits on Bombyx mori nucleopolyhedrovirus (BmNPV) polyhedral protein was detected by zymography technique. A complete inhibition of BmNPV infection to silkworms was observed by the oral administration assay of the SE-RFP. Here, it is proposed that the SE-RFP prevents the initial infection of BmNPV to silkworms by obliterating the polyhedral protein. This is the first report on a silkworm red fluorescent protein that exhibits a protease activity on exposure to SDS. The present studies would help in understanding the antiviral mechanism of silkworm red fluorescent proteins.