We established conditions for inducing antigen-specific tolerance in Th2 lymphocytes by means of oral tolerance. Mice were continuously exposed to ovalbumin in their drinking water for a minimal period of 20 days and then immunized against antigen in either complete Freund's adjuvant or Al(OH)3. This feeding regimen tolerized both Th2 and Th1 responses as shown by diminished proliferation, cytokine secretion (IL-4, IL-2 and IFN-gamma) and specific cytokine mRNA expression (IL-4, IL-2 and IFN-gamma) in vitro, as well as by absence of specific antibody production (IgG1, IgG2a, IgG2b and IgE) in vivo. Conditions for generating Th2 lymphocyte tolerance were different from those required to generate tolerance in Th1 lymphocytes: these included extended, continuous exposure to high dosages of antigen, rather than a single or intermittent feeding regimen which was sufficient to induce tolerance in Th1 lymphocytes. These findings suggest that continuous oral exposure to a tolerogen may be a biologically relevant strategy to tolerize both Th1- and Th-dependent responses, and extend the potential clinical use of oral tolerance to ailments mediated by Th2 lymphocytes.