The influence of prolonged intestinal antigen exposure on the immune response in humans was investigated. Two groups of volunteers were vaccinated orally with live Salmonella typhi Ty21a given in enteric-coated capsules three (group 3 x E) or six (group 6 x E) at 2-day intervals. The immune response was followed for 1 month by enumerating the antibody-secreting cells (ASC) in the peripheral blood. Soon after vaccination specific ASC were observed in the blood of all volunteers. In group 3 x E, the response peaked on day 5 or 7 and had faded away by day 14. In group 6 x E, by contrast, there was no clear single peak of the response, and the ASC numbers were high in several consecutive measurements. On day 14, considerable numbers of ASC were still detected in all cases; the responses had mostly faded away by day 22. These results show that prolonged exposure to antigen in the intestine induces a prolonged response of specific ASC in peripheral blood. This is an important prerequisite for the application of the ASC assay to study mucosal infections, in which the actual time of onset is often unknown. In addition, the findings suggest that the ASC assay might offer new possibilities for assessing the persistence of microbial antigens in infections.