E2-CD154 subunit vaccine candidate is safe and protects swine from Classical Swine Fever (CSF). However, its safety and immunogenicity in pregnant sows, and the capacity of maternal derived neutralizing antibodies (MDNA) to protect the offspring is yet to be demonstrated. The aim of this study was to evaluate the safety and immunogenicity of E2-CD154 in pregnant sows, and the capacity of MDNA to protect the offspring. Seventeen pregnant sows were vaccinated twice with E2-CD154 in either the first or the second third of pregnancy. Pregnancy and litter parameters were compared with a control group of non-vaccinated sows. Neutralizing antibodies (NAb) were monitored. The time course of MDNA was assessed in a group of six piglets born to an E2-CD154 immunized sow, and the animals were challenged with CSFV at day 63 after birth. No local or systemic adverse effects were found. Neither abortions, nor congenital malformations, nor stillbirths were observed. All sows develop high NAb titers after the first immunization. Piglets born to an E2-CD154 vaccinated sow still showed MDNA titers of 1:100 at day 63 after birth. Five animals were negative for virus isolation after challenge, and showed neither signs of CSF, nor macroscopic lesions in the organs. The other piglet was positive for CSFV isolation, and macroscopic lesions were observed in the spleen, although no clinical signs of CSF other than fever were detected. E2-CD154 vaccine candidate was safe and immunogenic in pregnant sows, and the passive immunity transmitted to the offspring was still protective by day 63 after birth.