The efficacy of the radiation-attenuated schistosome vaccine in eliciting protective immunity was investigated in the vervet Cercopithecus aethiops. Three groups of test animals received one, three, or five exposures to 5,000-9,000 cercariae attenuated with 30 krad of gamma radiation from a 137Cs source, while a fourth group served as challenge controls. After a single vaccination, no statistically significant protection was found; after three vaccinations it reached its highest peak (48%) and five exposures resulted in reduced protection (39%). Examination of immunologic parameters supported these findings, with proliferative responses of peripheral blood lymphocytes being greatest in the group vaccinated three times. Specific immunoglobulin G (IgG) levels also peaked after three vaccinations, with clear evidence of a reduction after the fourth and fifth exposures. There was a clear correlation (r = 0.66) between the antibody level at the time of challenge and the protection observed in individual vervets. These data demonstrate that protective immunity to Schistosoma mansoni can be achieved with the attenuated vaccine in a highly susceptible nonhuman primate (i.e., 82% maturation of penetrant cercariae was recorded in challenge control animals in this study). However, they also indicate that there is a ceiling to this protection. Furthermore, increasing the number of vaccinations beyond a certain point, instead of boosting protection may cause it to diminish, possibly due to the induction of immunoregulatory mechanisms.