Background: Classical swine fever (CSF) is one of the most devastating pig diseases that affect the swine industry worldwide. Besides stamping out policy for eradication, immunization with vaccines of live attenuated CSF or the CSF-E2 subunit is an efficacious measure of disease control. However, after decades of efforts, it is still hard to eliminate CSF from endemically affected regions and reemerging areas. Most of previous studies demonstrated the efficacy of different CSF vaccines in laboratories under high containment conditions, which may not represent the practical performance in field farms. The inadequate vaccine efficacy induced by unrestrained factors may lead to chronic or persistent CSF infection in animals that develop a major source for virus shedding among pig populations. In this study, a vaccination-challenge-cohabitation trial on specific-pathogen-free (SPF) pigs and long-term monitoring of sows and piglets were used to evaluate the efficacy and the impact of maternally derived antibody (MDA) interference on CSF vaccines in farm applications.Results: The trials demonstrated higher neutralizing antibody (NA) titers with no clinical symptoms and significant pathological changes in the CSF-E2 subunit vaccine immunized group after CSFV challenge. Additionally, none of the sentinel pigs were infected during cohabitation indicating that the CSF-E2 subunit vaccine could provoke adequate acquired immunity to prevent horizontal transmission. In field farm applications, the CSF-E2 subunit vaccine significantly reduced CSF viral RNA detection via saliva monitoring in a sow population that was routinely immunized with live attenuated CSF vaccine long term. Moreover, no adverse effects and an average of higher, long-lasting and consistent NA level could be detected in sows immunized with CSF-E2 subunit vaccine before parturition. Furthermore, early application of the CSF-E2 subunit vaccine in 3-week-old piglets illustrated no MDA interference on primary immunization whereas interference of MDA was noted in piglets vaccinated with live attenuated CSF.Conclusions: The CSF-E2 subunit vaccine demonstrated more flexibility and efficacy for immunization in both pregnant sows and piglets. These advantages could provide a novel approach to avoid possible virus shedding in sow population and MDA interference in piglets for control of CSF in field farm applications.