Classical swine fever virus (CSFV) causes significant losses in pig industry in many countries in Asia and Europe. The E2 glycoprotein of CSFV is the main target for neutralizing antibodies. Recently, the replicon of alphaviruses, such as Semliki Forest virus (SFV), has been developed as replicative expression vectors for gene delivery. In this study, we constructed a plasmid DNA based on SFV replicon encoding the E2 glycoprotein of CSFV and evaluated its efficacy in rabbits and pigs. The results showed that the animals immunized with the DNA vaccine developed CSFV-specific neutralizing antibodies and were protected from virulent or lethal challenge. This demonstrates that the SFV replicon-derived DNA vaccine can be a potential marker vaccine against CSFV infections.