Pretreatment of mice with anti-asialo GM1, which has been shown to deplete NK cytolytic activity without affecting cytotoxic T cells or macrophages, increased the weak anti-PPS 6 responses of adult mice to levels similar to that of their anti-PPS 3 responses, and increased the weak-to-absent anti-PPS 3 and anti-PPS 6 responses of weanling mice to the same levels as achieved by adult mice. By contrast, pretreatment with poly(IC), which augments NK activity, resulted in a 14-fold reduction in the anti-PPS 3 responses of adult mice. The enhancement of anti-PPS responses in mice treated with anti-asialo GM1 was due to inactivation or depletion of NK cells, and not T suppressor cells, since this enhancement occurred in athymic nude mice as well as in euthymic mice. In addition, strains of mice with low or absent endogenous NK activity were found to have considerably stronger anti-PPS responses than strains of mice with normal NK activity. NK depletion enhanced anti-PPS 6 IgM but not IgG response, and resulted in a true increase in antibody production rather than an alteration in the time course of the response. These findings indicate that NK cells physiologically downregulate anti-PPS responses, and that age-dependent and type-specific variations in these responses are primarily determined by NK regulatory effects.