A double-blind placebo-controlled clinical trial evaluated the immunogenicity of hepatitis B surface antigen (HBsAg) expressed in potatoes and delivered orally to previously vaccinated individuals. The potatoes accumulated HBsAg at approximately 8.5 microg/g of potato tuber, and doses of 100 g of tuber were administered by ingestion. The correlate of protection for hepatitis B virus, a nonenteric pathogen, is blood serum antibody titers against HBsAg. After volunteers ate uncooked potatoes, serum anti-HBsAg titers increased in 10 of 16 volunteers (62.5%) who ate three doses of potatoes; in 9 of 17 volunteers (52.9%) who ate two doses of transgenic potatoes; and in none of the volunteers who ate nontransgenic potatoes. These results were achieved without the coadministration of a mucosal adjuvant or the need for buffering stomach pH. We conclude that a plant-derived orally delivered vaccine for prevention of hepatitis B virus should be considered as a viable component of a global immunization program.