Currently live attenuated porcine reproductive and respiratory syndrome (PRRS) and classical swine fever (CSF) vaccines are widely used in Chinese swine herds. However, the mutual effects of vaccination procedures and severe stress caused by successive vaccinations harm piglets and make it difficult to stimulate robust and effective immune responses. In our previous study, a recombinant PRRS virus (PRRSV) vectored vaccine candidate rPRRSV-E2, which expresses CSF virus (CSFV) E2 protein, has been demonstrated being able to protect piglets against lethal challenge of highly-pathogenic (HP)-PRRSV and CSFV. In this study, we determine whether preexisting maternally derived antibodies (MDA) interfere with the immune efficacy of rPRRSV-E2. 8 experimental groups of piglets, with or without PRRSV MDAs or CSFV MDAs were immunized with a single dose of 10⁵ TCID₅₀ rPRRSV-E2 or DMEM and challenged with HP-PRRSV or CSFV. Clinical characteristics, PRRSV- or CSFV-specific antibodies, viremia and pathological changes were monitored, examined and analyzed. The results showed that rPRRSV-E2-vaccinated piglets, either with or without MDAs directed against PRRSV or CSFV were completely protected from the lethal challenge of HP-PRRSV or CSFV. These results demonstrate that the MDAs do not interfere with the immune efficacy of rPRRSV-E2, which indicates that rPRRSV-E2 could have great significance in the effective prevention and control of HP-PRRSV and CSFV.