Prevention of hepatitis B, one of the most prevalent human diseases, still requires cheap and commonly available vaccines. Oral vaccines, including plant-based formulations, have been considered as alternatives or supplements for standard injection vaccines, due to the assumed low-cost production and simplified vaccination. Although plant production of HBV antigens is sufficiently efficient, despite almost 20 years of research still no anti-HBV plant-based vaccine has been developed. The basic difficulty has been to elaborate an effective immunisation procedure. Immunisation by parenteral priming and oral boosting with raw plant tissue adjuvanted with the cholera toxin, although effective, seemed to be unfeasible and controversial. Exclusively oral immunisation using lyophilised tissue, despite its appropriate form, appeared also impractical because of too low efficiency. Oral tolerance turned out to be the main barrier for anti-HBV plant-based vaccines. Based on previous results and knowledge on the mucosal immune system, a possible vaccine may consist of two components, parenteral for priming and oral for boosting. Probably the oral constituent could independently serve for further booster vaccinations. Both vaccine components can be produced in plants and used after some processing - purification for the injection constituent and lyophilisation for the oral one. Lyophilised tissue can be converted into tablets, capsules, etc. Previous and recent data show that the injection-oral immunisation regime may be efficient. A combination of parenteral and oral vaccination offers good prospects for a truly efficacious plant-derived anti-HBs vaccine and even a partial substitution of parenteral vaccines by an oral formula may prove to be economically reasonable.