A recombinant Plasmodium vivax circumsporozoite (CS) antigen representing approximately 70% of the CS protein was expressed in yeast and adsorbed onto aluminum hydroxide for use as a malaria vaccine. In a study of safety and immunogenicity, 30 volunteers were divided into four groups of 5, 5, 10, and 10 individuals, and inoculated intramuscularly with 50, 100, 200, or 400 micrograms of vaccine, respectively. Primary vaccinations were followed by two booster immunizations at six weeks and six months. Overall, the vaccine was well tolerated. Following the third vaccination, one volunteer developed acute hepatitis of uncertain etiology that resolved without sequelae. All volunteers in the 400-micrograms group, and six of 10 in the 200-micrograms group generated IgG against P. vivax CS protein, as determined by Western blot using recombinant CS protein. However, the magnitude of the antibody response measured by indirect immunofluorescence of intact sporozoites or enzyme-linked immunosorbent assay against the recombinant protein was low, and responses could not be boosted. Antigen-driven replication studies using peripheral blood lymphocytes failed to detect proliferative responses specific to peptide sequences represented in the recombinant vaccine, except in one volunteer. Minimal humoral and cell-mediated immune responses developed in most recipients who received this recombinant CS vaccine.