We propose through a sequence and structural-pattern analysis that a protein domain of undefined function encoded by the enveloped RNA flavi- and pestiviruses is a Ser active-center enzyme related to the cellular trypsin family. A further homology is emphasized with the group of (Cys active-center) viral proteases encoded by nonenveloped RNA viruses of the picorna-, como-, nepo-, and potyvirus classes. Structural modeling of the putative flaviviral protease domain suggests amino acids that are crucial for catalytic activity and substrate binding.